N-aryl-2-oxazolidinone-5-carboxamides and their derivatives

ABSTRACT

The present invention provides antibacterial agents having the formulae I, II, and III described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 10/646,440filed, Aug. 22, 2003 now U.S. Pat. No. 7,141,588, which is acontinuation-in-part of U.S. Ser. No. 10/373,286, filed Feb. 24, 2003now U.S. Pat. No. 6,919,329, which in turns claims the benefit of U.S.Ser. No. 60/359,495 filed Feb. 25, 2002, under 35 USC 119(e)(i).

FIELD OF THE INVENTION

The present invention relates to novelN-Aryl-2-oxazolidinone-5-carboxamides, derivatives thereof, and theirpreparations. These compounds have potent antibacterial activity.

BACKGROUND OF THE INVENTION

The oxazolidinone antibacterial agents are a novel synthetic class ofantimicrobials with potent activity against a number of human andveterinary pathogens, including gram-positive aerobic bacteria such asmultiply-resistant staphylococci and streptococci, anaerobic organismssuch as bacteroides and clostridia species, and acid-fast organisms suchas Mycobacterium tuberculosis and Mycobacterium avium.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds of formula I

or a pharmaceutically acceptable salt thereof wherein:

A is a structure i, ii, or iii

C is aryl or heteroaryl, wherein each of the aryl and heteroaryl areoptionally substituted with 1-3 of R₂;

B is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, het and substitutedhet, or B and one R₂, if present, together, with the phenyl carbon atomsto which B and the one R₂ are bonded, form a het, the het optionallybeing a substituted het,

-   -   provided that

when C is phenyl optionally substituted with R₂ that B is not

Q is independently selected from H, C₁-C₆ alkyl, —O—C₁-C₆ alkyl, phenyl,benzyl, —OH, CF₃, CCl₃, —NR₃R₃, —C₁-C₆ alkylene-NR₃R₃, C₁-C₆alkylene-(CH₂phenyl)-NR₃R₃, C₁-C₆ alkylene-(CH₂benzyl)-NR₃R₃, and

R₁ is selected from H, —OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino,substituted alkyl, substituted alkoxy, and substituted alkenyl;

Each R₂ is independently selected from H, alkyl, amino, NO₂, —CN, halo,and substituted alkyl;

Each R₃ is independently selected from H or C₁-C₆ alkyl; and

W₂ is O or S.

Embodiments of this aspect of the invention may include one or more ofthe following features. Each R₂ is independently selected from H, F, Cl,Br, CN, NH₂, NO₂, CF₃, and CH₃. The structure of A is

R₁ is H, —NH₂, —OH, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ alkoxy, or C₂₋₄alkenyl, the alkyl, alkoxy and alkenyl each optionally being substitutedwith one or more halo, —OH, —CN. R₁ is H, —OH, —CH₂—CH═CH₂, methyl,ethyl, propyl, —CH₂—CH₂F, —CH₂—CH₂OH, or methoxy. B is het orsubstituted het such as morpholinyl, piperazinyl, pyridyl,thiomorpholinyl, 3,6-dihydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl,3,6-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, azetidinyl,5,6-dihydro-4H-[1,3,4]thiadiazinyl, 2,5-dihydro-1H-pyrrolyl,3,4-dihydro-1(2H)-pyridinyl, tetrahydropyridyl,5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3-dihydro-4H-1,4-thiazinyl,each of the morpholinyl, piperazinyl, pyridyl, thiomorpholinyl,3,6-dihydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl,3,6-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, azetidinyl,5,6-dihydro-4H-[1,3,4]thiadiazinyl, 2,5-dihydro-1H-pyrrolyl,3,4-dihydro-1(2H)-pyridinyl, tetrahydropyridyl,5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3-dihydro-4H-1,4-thiazinylbeing optionally substituted with 1-4 groups selected from ═O, alkyl,substituted alkyl, amino, substituted amino, —OH, ═NOH, ═NC₁₋₄ alkyl,and halo. B is selected from

One R₂ is hydrogen and the other R₂ is F. Both R₂ substituents are F.One R₂ and B together form a het. R₂ and B form —S—C(O)—N(Q₅₀),—O—C(O)—N(Q₅₀), —N(Q₅₀)—HCQ₅₀-CH₂—, —NQ₅₀-C(O)—CH₂—O—,—NQ₅₀-C(O)—CF₂—O—, —NQ₅₀-C(O)—CH₂—S—, —NQ₅₀-C(O)—CF₂—S—,—NQ₅₀-C(S)—CH₂—S—, —NQ₅₀-C(O)—CH₂—CH₂—, —CH₂—CH₂—NQ₅₀-CH₂—CH₂—, or—CH₂—NQ₅₀-CH₂—CH₂—CH₂—, where Q₅₀ is H or C₁₋₄ alkyl optionallysubstituted with 1-3 of ═O, or —OH. Q₅₀ is methyl, isopropyl, ethyl,formyl, acetyl, or —C(O)—CH₂OH.

In another aspect, the invention provides compounds of formula II

or a pharmaceutically acceptable salt thereof wherein:

A is a structure i, ii, or iii

B is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, het, and substitutedhet, or B and one R₂ together, with the phenyl carbon atoms to which Band the one R₂ are bonded, form a het, the het optionally being asubstituted het,

-   -   provided that

B is not

Q is independently selected from H, C₁-C₆ alkyl, —O—C₁-C₆ alkyl, phenyl,benzyl, —OH, CF₃, CCl₃, —NR₃R₃, —C₁-C₆ alkylene-NR₃R₃, C₁-C₆alkylene-(CH₂phenyl)-NR₃R₃, C₁-C₆ alkylene-(CH₂benzyl)-NR₃R₃, and

R₁ is selected from H, —OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino,substituted alkyl, substituted alkoxy, and substituted alkenyl;

Each R₂ is independently selected from H, alkyl, amino, NO₂, —CN, halo,and substituted alkyl;

Each R₃ is independently selected from H or C₁-C₆ alkyl; and

W₂ is O or S.

In another aspect the invention features a compound of formula III

or a pharmaceutically acceptable salt thereof wherein:

-   A is a structure i, ii, or iii

-   B is

-   -   l) a diazinyl group optionally substituted with X and Y,    -   m) a triazinyl group optionally substituted with X and Y,    -   n) a quinolinyl group optionally substituted with X and Y,    -   o) a quinoxalinyl group optionally substituted with X and Y,    -   p) a naphthyridinyl group optionally substituted with X and Y,

B and one R₂ are taken together to form

-   A¹ is    -   a) H—, or    -   b) CH₃;-   A² is    -   a) H—,    -   b) HO—,    -   c) CH₃—,    -   d) CH₃O—,    -   e) R¹⁰²O—CH₂—C(O)—NH—    -   f) R₁₀₃O—C(O)—NH—,    -   g) (C₁-C₂)alkyl-O—C(O)—,    -   h) HO—CH₂—,    -   i) CH₃O—NH—,    -   j) (C₁-C₃)alkyl-O₂C—    -   k) CH₃—C(O)—,    -   l) CH₃—C(O)—CH₂—,

-   A¹ and A² taken together are:

-   A³ represents any 5-10 membered aryl ring or aromatic het, the het    having 1-4 heteroatoms selected from O, S, or N;-   B₁ is    -   a) —N═C(H)—C(H)═C(H)—, or    -   b) —C(H)═N—C(H)═C(H)—;-   D₁ is    -   a) O,    -   b) S(O)_(i), or    -   c) —N(R₃₀₄)—;-   D₂ is    -   a) O, or    -   b) —N(R₃₀₄)—;-   E is    -   a) NR₃₉,    -   b) —S(═O)_(i),    -   c) O, or    -   d) —S(═O)(═NR₃₁₅);-   F₁ is    -   a) O,    -   b) S,    -   c) NH,    -   d) N—OH,    -   e) N—O—C₁₋₄ alkyl,    -   f) N—OC(O)—C₁₋₄ alkyl, or    -   g) N—C₁₋₄alkyl;-   K₁ is    -   a) O,    -   b) S, or    -   c) —NR₃₀₅—;-   M is    -   a) H,    -   b) C₁₋₈ alkyl,    -   c) C₃₋₈ cycloalkyl,    -   d) —(CH₂)_(m)OR₁₃, or    -   e) —(CH₂)_(h)—NR₂₁R₂₂;-   T₁ is    -   a) —O—,    -   b) —NR₃₀₆    -   c) —S(O)_(i)—,    -   d) —C(R₂)—, or    -   e) —C(O)—;-   T₂ is    -   a) —O—,    -   b) —NR₃₀₇—,    -   c) —S(O)_(i)—,    -   d) —C(O)—, or    -   e) —C(R₂)₂—;-   Each U₁, U₂, and U₃ is independently selected from    -   a) —C(R₁)₂—,    -   b) —NR₃₉—,    -   c) —O—, or    -   d) —S(O)_(i)—;-   V is    -   a) O,    -   b) CH₂, or    -   c) NR₈₇;-   W is    -   a) CH, or    -   b) N;-   W₁ is    -   a) —NH—,    -   b) O, or    -   c) S;-   W₂ is O or S;-   X is    -   a) H,    -   b) —CN,    -   c) —OR₂₇,    -   d) halo,    -   e) —NO₂,    -   f) tetrazolyl optionally substituted with C₁₋₄alkyl,    -   g) —SH,    -   h) —S(═O)R₄,    -   i) —SC(═O)R₇,    -   j) —C(═O)R₂₅,    -   k) —C(═O)NR₂₇R₂₈,    -   l) —C(═NR₂₉)R₂₅,    -   m) —C(R₂₅)(R₂₈)—OR₁₃,    -   n) —C(R₂₅)(R₂₈)—OC(═O)R₁₃,    -   o) —C(R₂₈)(OR₁₃)—(CH₂)_(h)—NR₂₇R₂₈,    -   p) —NR₂₇R₂₈,    -   q) —N(R₂₇)C(═O)R₇,    -   r) —N(R₂₇)—S(═O)_(i)R₇,    -   s) —C(OR₁₄)(OR₁₅)R₂₈,    -   t) —C(R₂₅)(R₁₆)—NR₂₇R₂₆,    -   u) —C₁₋₈ alkyl substituted with one or more halos, OH, ═O other        than at alpha position, —S(═O)_(i)R₁₇, —NR₂₇R₂₈, C₂₋₅ alkenyl,        C₂₋₅ alkynyl, or C₃₋₈ cycloalkyl, or    -   v) -Het optionally substituted with R₂, ═O or ═S;-   Y is    -   a) H,    -   b) F,    -   c) Cl,    -   d) Br,    -   e) C₁₋₃ alkyl, or    -   f) NO₂;-   Each Y₁ and Y₂ is independently    -   a) CH, or    -   b) N provided that - - - is absent, or    -   c) C when - - - is present;-   Z is    -   a) O,    -   b) S, or    -   c) NM;-   Z₁ is    -   a) —CH₂—,    -   b) —CH(R¹⁰⁴)—CH₂—,    -   c) —C(O)—, or    -   d) —CH₂CH₂CH₂—;-   Z² is    -   a) —S(O)i-,    -   b) —O—,    -   c) —N(R¹⁰⁷)—, or    -   d) —S(═O)(═NR³¹⁵)—;-   Z³ is    -   a) —S(O)i-, or    -   b) —O—,-   Z³ is    -   a) —S(═O)_(i)-, or    -   b) NR³⁰³—;-   Z is    -   a) —O—,    -   b) —NH—,    -   c) —CH₂—,    -   d) —C(halo)₂-, or    -   e) —S(═O)_(j)—;-   Z⁶ is    -   a) S(═O)_(i),    -   b) S(═NR³¹⁵), or    -   c) S(═NR³¹⁵)(═O);-   Z⁷ is    -   a) N,    -   b) CR¹¹⁰,    -   c) CR¹¹⁵, or    -   d) CR¹¹⁶;-   Z is    -   a) O, or    -   b) S;-   R₁ is    -   a) H,    -   b) —OH,    -   c) C₁₋₆ alkyl optionally substituted with one or more halos,        —OH, —CN, aryl, het, alkoxy, substituted aryl or substituted        het,    -   d) C₁₋₆ alkoxy optionally substituted with one or more halos,        —OH, —CN, aryl, het, substituted aryl or substituted het,    -   e) C₂₋₆ alkenyl optionally substituted with aryl, het,        substituted aryl or substituted het,    -   f) —NH₂, or    -   g) C₃₋₅ cycloalkyl;-   R₂ is    -   a) H,    -   b) C₁₋₂ alkyl optionally substituted with one or more halos,    -   c) —NH₂,    -   d) —NO₂,    -   e) —CN, or    -   f) halo;-   R₄ is    -   a) H    -   b) C₁₋₄ alkyl optionally substituted with one or more halos, OH,        CN, NR₁₀R₁₁, or —CO₂R₁₃,    -   c) C₂₋₄ alkenyl,    -   d) —NR₁₆R₁₈,    -   e) —NHC(═O)R₇,    -   f) —NR₂₀C(═O)R₇,    -   g) —N(R₁₇)₂,    -   h) —NR₁₆R₁₇, or    -   i) —NR₁₇R₂₀;-   R₅ and R₆ at each occurrence are the same or different and are    -   a) C₁₋₂ alkyl, or    -   b) R₅ and R₆ taken together are —(CH₂)_(k)—;-   R₇ is    -   a) C₁₋₄ alkyl optionally substituted with one or more halos;-   R₁₀ and R₁₁ at each occurrence are the same or different and are    -   a) H,    -   b) C₁₋₄ alkyl, or    -   c) C₃₋₈ cycloalkyl;-   R₁₃ is    -   a) H, or    -   b) C₁₋₄ alkyl;-   R₁₄ and R₁₅ at each occurrence are the same or different and are    -   a) C₁₋₄ alkyl, or    -   b) R₁₄ and R₁₅ taken together are —(CH₂)₁—;-   R₁₆ is    -   a) H,    -   b) C₁₋₄ alkyl, or    -   c) C₃₋₈ cycloalkyl;-   R₁₇ is    -   a) C₁₋₄ alkyl, or    -   b) C₃₋₈ cycloalkyl;-   R₁₈ is    -   a) H,    -   b) C₁₋₄ alkyl,    -   c) C₂₋₄ alkenyl,    -   d) C₃₋₄ cycloalkyl,    -   e) —OR₁₃ or    -   f) —NR₂₁R₂₂;-   R₂₀ is a physiologically acceptable cation, such as sodium,    potassium, lithium, calcium or magnesium;-   R₂₁ and R₂₂ at each occurrence are the same or different and are    -   a) H,    -   b) C₁₋₄ alkyl, or    -   c) R₂₁ and R₂₂ taken together are —(CH₂)_(m)—;-   R₂₅ is    -   a) H,    -   b) C₁₋₈ alkyl optionally substituted with one or more halos,        C₃₋₈ cycloalkyl, C₁₋₄ alkyl substituted with one or more of        —S(═O)_(i)R₁₇, —OR₁₃, or OC(═O)R₁₃, NR₂₇R₂₈, or    -   c) C₂₋₅ alkenyl optionally substituted with —C(O)H, or CO₂R₁₃;-   R₂₆ is    -   a) R₂₈, or    -   b) —NR₂₇N₂₈;-   R₂₇ and R₂₈ at each occurrence are the same or different and are    -   a) H,    -   b) C₁₋₈ alkyl,    -   c) C₃₋₈ cycloalkyl,    -   d) —(CH₂)_(m)OR₁₃,    -   e) —(CH₂)_(h)—NR₂₁R₂₂, or    -   f) R₂₇ and R₂₈ taken together are —(CH₂)₂O(CH₂)₂—,        —(CH₂)_(h)CH(COR₇)—, or —(CH₂)₂N(CH₂)₂(R₇);-   R₂₉ is    -   a) —NR₂₇R₂₈,    -   b) —OR₂₇, or    -   c) —NHC(═O)R₂₈;-   R₃₀ is    -   a) H, or    -   b) C₁₋₄ alkyl optionally substituted with one or more halos, OH,        C₁₋₄ alkoxy, CN, SH, NH₂, —OR₃₁, —NHR₃₁, —N(R₃₁)₂, or        —S(O)_(i)R₃₁;-   R₃₁ is    -   a) C₁₋₄ alkyl,    -   b) —C(O)C₁₋₄ alkyl,    -   c) —C(O)OC₁₋₄ alkyl,    -   d) —C(O)NH₂,    -   e) —C(O)NHC₁₋₄ alkyl, or    -   f) —SO₂C₁₋₄ alkyl;-   R₃₈ is    -   a) H,    -   b) C₁₋₆ alkyl,    -   c) —(CH₂)_(q)-aryl, or    -   d) halo;-   R₃₉ is    -   a) H,    -   b) C₁₋₆ alkyl optionally substituted with one or more OH, halo,        or —CN,    -   c) —(CH₂)_(w)-aryl,    -   d) —CO₂R₄₀,    -   e) —COR₄₁,    -   f) —C(═O)—(CH₂)_(q)—C(═O)R₄₀,    -   g) —S(═O)₂—C₁₋₆ alkyl,    -   h) —S(═O)₂—(CH₂)_(q)-aryl, or    -   i) —(C═O)_(j)-Het;-   R₄₀ is    -   a) H,    -   b) C₁₋₆ alkyl optionally substituted with one or more OH, halo,        or —CN,    -   c) —(CH₂)_(q)-aryl, or    -   d) —(CH₂)_(q)—OR₄₂;-   R₄₁ is    -   a) C₁₋₆ alkyl optionally substituted with one or more OH, halo,        —OP(O)(OH)₂, —OP(OH)₂, or —CN,    -   b) —(CH₂)_(q)-aryl, or    -   c) —(CH₂)_(q)—OR₄₂;-   R₄₂ is    -   a) H,    -   b) C₁₋₆ alkyl,    -   c) —(CH₂)_(q)-aryl, or    -   d) —C(═O)—C₁₋₆ alkyl;-   R₄₉ and R₅₀ at each occurrence are the same or different and are    -   a) H,    -   b) C₁₋₄ alkyl,    -   c) C₅₋₆ cycloalkyl, or    -   d) R₄₉ and R₅₀ taken together with the nitrogen atom is a 5-,        6-membered saturated heterocyclic moiety which optionally has a        further hetero atom selected from the group consisting of S, N,        and O, and can in turn be optionally substituted with, including        on the further nitrogen atom, C₁₋₃ alkyl, or C₁₋₃ acyl;-   R₅₁ is    -   a) carboxyl,    -   b) halo,    -   c) —CN,    -   d) mercapto,    -   e) formyl,    -   f) CF₃,    -   g) —NO₂,    -   h) C₁₋₆ alkoxy,    -   i) C₁₋₆ alkoxycarbonyl,    -   j) C₁₋₆ alkythio,    -   k) C₁₋₆ acyl,    -   l) C₁₋₆ alkyl optionally substituted with OH, C₁₋₅ alkoxy, C₁₋₅        acyl, or —NR₄₉R₅₀,    -   m) phenyl,    -   n) —C(═O)NR₅₂R₅₃,    -   o) —NR₄₉R₅₀,    -   p) —N(R₅₂)(—SO₂R₅₄),    -   q) —SO₂—NR₅₂R₅₃, or    -   r) —S(═O)_(i)R₅₄;-   R₅₂ and R₅₃ at each occurrence are the same or different and are    -   a) H,    -   b) C₁₋₆ alkyl, or    -   c) phenyl;-   R₅₄ is    -   a) C₁₋₄ alkyl, or    -   b) phenyl optionally substituted with C₁₋₄ alkyl;-   R₇₃ and R₇₄ at each occurrence are the same or different and are    -   a) H,    -   b) carboxyl,    -   c) halo,    -   d) —CN,    -   e) mercapto,    -   f) formyl,    -   g) CF₃,    -   h) —NO₂,    -   i) C₁₋₆ alkoxy,    -   j) C₁₋₆ alkoxycarbonyl,    -   k) C₁₋₆ alkythio,    -   l) C₁₋₆ acyl,    -   m) —NR₇₈R₇₉,    -   n) C₁₋₆ alkyl optionally substituted with OH, C₁₋₅ alkoxy, C₁₋₅        acyl, —NR₇₈R₇₉, —N(phenyl)(CH₂—CH₂—OH), —O—CH(CH₃)(OCH₂CH₃), or        —O-phenyl-[para-NHC(═O)CH₃],    -   o) C₂₋₈ alkenylphenyl optionally substituted with R₅₁,    -   p) phenyl optionally substituted with R₅₁, or    -   q) a 5-, or 6-membered saturated or unsaturated heterocyclic        moiety having one to three atoms selected from the group        consisting of S, N, and O, optionally substituted with R₅₁;-   R₇₈ and R₇₉ at each occurrence are the same or different and are    -   a) H,    -   b) C₁₋₄ alkyl,    -   c) phenyl, or    -   d) R₇₈ and R₇₉ taken together with the nitrogen atom is a 5-,        6-membered saturated heterocyclic moiety which optionally has a        further hetero atom selected from the group consisting of S, N,        and O, and can in turn be optionally substituted with, including        on the further nitrogen atom, C₁₋₃ alkyl, or C₁₋₃ acyl;-   R₈₀ is    -   a) H,    -   b) formyl,    -   c) carboxyl,    -   d) C₁₋₆ alkoxycarbonyl,    -   e) C₁₋₈ alkyl,    -   f) C₂₋₈ alkenyl, wherein the substituents (e) and (f) can be        optionally substituted with OH, halo, C₁₋₆ alkoxy, C₁₋₆ acyl,        C₁₋₆ alkylthio or C₁₋₆ alkoxycarbonyl, or phenyl optionally        substituted with halo,    -   g) an aromatic moiety having 6 to 10 carbon atoms optionally        substituted with carboxyl, halo, —CN, formyl, CF₃, —NO₂, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, C₁₋₆ alkylthio, or C₁₋₆        alkoxycarbonyl;    -   h) —NR₈₁R₈₂,    -   i) —OR₉₀,    -   j) —S(═O)_(i)—R₉₁, or    -   k) —SO₂—N(R₉₂)(R₉₃);-   R₈₁ and R₈₂ at each occurrence are the same or different and are    -   a) H,    -   b) C₃₋₆ cycloalkyl,    -   c) phenyl,    -   d) C₁₋₆ acyl,    -   e) C₁₋₈ alkyl optionally substituted with OH, C₁₋₆ alkoxy which        can be substituted with OH, a 5-, or 6-membered aromatic        heterocyclic moiety having one to three atoms selected from the        group consisting of S, N, and O, phenyl optionally substituted        with OH, CF₃, halo, —NO₂, C₁₋₄ alkoxy, —NR₈₃R₈₄, or

-   R₈₃ and R₈₄ at each occurrence are the same or different and are    -   a) H, or    -   b) C₁₋₄ alkyl;-   R₈₅ is    -   a) OH,    -   b) C₁₋₄ alkoxy, or    -   c) —NR₈₈R₈₉;-   R₈₆ is    -   a) H, or    -   b) C₁₋₇ alkyl optionally substituted with indolyl, OH,        mercaptyl, imidazoly, methylthio, amino, phenyl optionally        substituted with OH, —C(═O)—NH₂, —CO₂H, or —C(═NH)—NH₂;-   R₈₇ is    -   a) H,    -   b) phenyl, or    -   c) C₁₋₆ alkyl optionally substituted by OH;-   R₈₈ and R₈₉ at each occurrence are the same or different and are    -   a) H,    -   b) C₁₋₅ alkyl    -   c) C₃₋₆ cycloalkyl, or    -   d) phenyl;-   R₉₀ is    -   a) C₁₋₈ alkyl optionally substituted with C₁₋₆ alkoxy or C₁₋₆        hydroxy,    -   C₃₋₆ cycloalkyl, a 6-membered aromatic optionally benzo-fused        heterocyclic moiety having one to three nitrogen atoms, which        can in turn be substituted with one or two —NO₂, CF₃, halo, —CN,        OH, C₁₋₅ alkyl, C₁₋₅ alkoxy, or C₁₋₅ acyl;

-   -   c) phenyl, or    -   d) pyridyl;

-   R₉₁ is    -   a) C₁₋₆alkyl,    -   b) C₂₋₁₆ alkenyl, wherein the substituents (a) and (b) can be        optionally substituted with C₁₋₆ alkoxycarbonyl, or a 5-, 6-,        7-membered aromatic heterocyclic moiety having one to three        atoms selected from the group consisting of S, N, and O,    -   c) an aryl having 6 to 10 carbon atoms, or    -   d) a 5-, 6-, 7-membered aromatic heterocyclic moiety having one        to three atoms selected from the group consisting of S, N, and        O, wherein the substituents (c) and (d) can be optionally        substituted with carboxyl, halo, —CN, formyl, CF₃, —NO₂, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, C₁₋₆ alkylthio, or C₁₋₆        alkoxycarbonyl;

-   R₉₂ and R₉₃ at each occurrence are the same or different and are    -   a) H,    -   b) phenyl,    -   c) C₁₋₆ alkyl, or    -   d) benzyl;

-   R¹⁰² is    -   a) H—,    -   b) CH₃—,    -   c) phenyl-CH₂—, or    -   d) CH₃C(O)—;

-   R¹⁰³ is    -   a) (C₁-C₃)alkyl-, or    -   b) phenyl-;

-   R¹⁰⁴ is    -   a) H—, or    -   b) HO—;

-   R¹⁰⁶ is    -   a) CH₃—C(O)—,    -   b) H—C(O)—,    -   c) Cl₂CH—C(O)—,    -   d) HOCH₂—C(O)—,    -   e) CH₃SO₂—,

-   -   g) F₂CHC(O)—,

-   -   i) H₃C—C(O)—O—CH₂—C(O)—,    -   j) H—C(O)—O—CH₂—C(O)—,

-   -   l) HC≡C—CH₂O—CH₂—C(O)—,    -   m) phenyl-CH₂—O—CH₂—C(O)—,    -   o) C₁₋₄alkyl-NH—C(S)—, or    -   p) C₁₋₄alkyl optionally substituted with one or more halo, CN,        NO₂, OH, SH, or NH₂;

-   R¹⁰⁷ is    -   a) R¹⁰²O—C(R¹¹⁰)(R¹¹¹)—C(O)—,    -   b) R¹⁰³O—C(O)—,    -   c) R¹⁰⁸—C(O)—,

-   -   f) H₃C—C(O)—(CH₂)₂—C(O)—,    -   g) R¹⁰⁹—SO₂—,

-   -   i) HO—CH₂—C(O)—,    -   j) R¹¹⁶—(CH₂)₂—,    -   k) R¹¹³—C(O)—O—CH₂—C(O)—,    -   l) (CH₃)₂N—CH₂—C(O)—NH—,    -   m) NC—CH₂—,    -   n) F₂—CH—CH₂—, or    -   o) R¹⁵⁰R¹⁵¹NSO₂

-   R¹⁰⁸ is    -   a) H—,    -   b) (C₁-C₄)alkyl,    -   c) aryl —(CH₂)_(n),    -   d) ClH₂C—,    -   e) Cl₂HC—,    -   f) FH₂C—,    -   g) F₂HC—,    -   h) (C₃-C₆)cycloalkyl, or    -   i) CNCH₂—

-   R¹⁰⁹ is    -   a) C₁-C₄alkyl,    -   b) —CH₂Cl    -   c) —CH₂CH═CH₂,    -   d) aryl, or    -   e) —CH₂CN;

-   R¹¹⁰ and R¹¹¹ are independently    -   a) H—,    -   b) CH₃—; or

-   R¹¹² is    -   a) H—,    -   b) CH₃O—CH₂O—CH₂—, or    -   c) HOCH₂—;

-   R¹¹³ is    -   a) CH₃—,    -   b) HOCH₂—,    -   c) (CH₃)₂N-phenyl, or    -   d) (CH₃)₂N—CH₂—;

-   R¹¹⁴ is    -   a) HO—,    -   b) CH₃O—,    -   c) H₂N—,    -   d) CH₃O—C(O)—O—,    -   e) CH₃—C(O)—O—CH₂—C(O)—O—,    -   f) phenyl-CH₂—O—CH₂—C(O)—O—,    -   g) HO—(CH₂)₂—O—,    -   h) CH₃O—CH₂—O—(CH₂)₂—O—, or    -   i) CH₃O—CH₂—O—;

-   R¹¹⁵ is    -   a) H—, or    -   b) Cl—;

-   R¹¹⁶ is    -   a) HO—    -   b) CH₃O—, or    -   c) F;

-   Each of R₁₁₇, R₁₁₈, R₁₁₉, and R₁₂₀ is independently selected from    -   a) H,    -   b) C₁-C₆alkyl,    -   c) substituted alkyl,    -   d) halo, or    -   e) R₁₁₇ and R₁₁₈ or R₁₁₉ and R₁₂₀ together are ═O;

-   R¹⁵⁰ and R¹⁵¹ are each independently    -   a) H,    -   b) C₁-C₄alkyl, or    -   c) R¹⁵⁰ and R¹⁵¹ taken together with the nitrogen atom, to which        R¹⁵⁰ and R¹⁵¹ are attached, form a monocyclic heterocyclic ring        having from 3 to 6 carbon atoms;

-   Each R₃₀₀, R₃₀₁, R₃₀₂, R₃₀₃, R₃₀₄, R₃₀₅, and R₃₀₆ is independently    selected from    -   a) H,    -   b) C₃₋₆ cycloalkyl optionally substituted with ═O,    -   c) C₁₋₆ alkoxy,    -   d) C₁₋₁₀ alkyl optionally substituted with one or more of R₃₁₀,    -   e) C₂₋₁₀ alkenyl optionally substituted with one or more of        R₃₁₀,    -   f) benzyloxycarbonyl,    -   g) aryl,    -   h) het,    -   i) —C(O)—NR₃₁₁R₃₁₂,    -   j) —S(O)₂—NR₃₁₁R₃₁₂,    -   k) —(O)_(i)SR₃₁₁,    -   l) —C(O)—R₃₁₀,    -   m) —C(S)—NR₃₁₁R₃₁₂,    -   n) —C(O)—H, or    -   o) —C(O)—C₁₋₄alkyl optionally substituted with one or more of        R₃₁₀;

-   Each R₃₀₇ is independently selected from    -   a) H,    -   b) C₃₋₆ cycloalkyl optionally substituted with ═O,    -   c) C₁₋₆ alkoxy,    -   d) C₁₋₁₀ alkyl optionally substituted with one or more of R₃₁₀,    -   e) C₂₋₁₀ alkenyl optionally substituted with one or more of        R₃₁₀,    -   f) benzyloxycarbonyl,    -   g) aryl,    -   h) het,    -   i) —C(O)—NR₃₁₁R₃₁₂,    -   j) —S(O)₂—NR₃₁₁R₃₁₂,    -   k) —(O)_(i)SR₃₁₁,    -   l) —C(O)—R₃₁₀,    -   m) —C(S)—NR₃₁₁R₃₁₂,    -   n) —C(O)—H,    -   o) —C(O)—C₁₋₄alkyl optionally substituted with one or more of        R₃₁₀, or    -   p) —C(N—O—C₁₋₄alkyl)-;

-   R₃₀₈ and R₃₀₉ are H or both R₃₀₈ and R₃₀₉ together form ═O or ═S;

-   R₃₁₀ is    -   a) —CN,    -   b) —N₃,    -   c) —CF₃,    -   d) pyridyl,    -   e) halo,    -   f) —OH,    -   g) —O(O)C₁-C₆alkyl,    -   h) —C₁₋₆ alkyloxycarbonyl,    -   i) —SH,    -   j) —NH₂;

-   Each R₃₁₁, and R₃₁₂ is independently selected from    -   a) H,    -   b) C₁₋₄ alkyl,    -   c) phenyl, or    -   d) R₃₁₁, and R₃₁₂ together with the N-atom to which they are        attached forms a 5- or 6-membered, saturated heterocyclic ring        optionally having one or more O, S, or N atoms in the ring, the        heterocyclic ring being optionally substituted with C₁₋₃ alkyl;

-   R₃₁₅ is    -   a) H,    -   b) C₁₋₄ alkyl optionally substituted with halo, —OH, C₁₋₈        alkoxy, amino, C₁₋₈ alkylamino, or C₁₋₈dialkylamino,    -   c) aryl-S(O)₂—,    -   d) C(═O)C₁₋₄alkyl,    -   e) C(═O)OC₁₋₄alkyl,    -   f) C(═O)NHR₃₂₀,    -   g) C(═S)NHR₃₂₀,    -   h) —OC(═O)C₁₋₄alkyl,    -   i) —S(O)_(i)C₁₋₄alkyl,    -   j) C₁₋₄ alkyl-O—C₁₋₄ alkyl, or    -   k) C₁₋₄ alkyl-S—C₁₋₄ alkyl;

-   R₃₂₀ is independently selected from    -   a) H, or    -   b) substituted alkyl;

-   Each R₃₂₅, R₃₂₆, R₃₂₇, and R₃₂₈ is independently selected from    -   a) H,    -   b) C₁-C₆alkyl,    -   c) substituted alkyl,    -   d) halo, or    -   e) R₃₂₅ and R₃₂₆ or R₃₂₇ and R₃₂₈ together are ═O, ═S, or        ═N—R₃₃₂, or    -   f) one of R₃₂₅ or R₃₂₆ and R₃₀₃, when Z₄ is —N(R₃₀₃), together        with the carbon and nitrogen atoms to which they are bound form        a 5-7 membered het containing one or more heteroatoms selected        from O, S, or N, the het being optionally substituted with one        or more of R₂, ═O, or ═S;

-   R₃₃₀ is    -   a) H, or    -   b) alkyl, or    -   c) substituted alkyl;

-   R₃₃₁ is    -   a) R₃₃₂,    -   b) Cl,    -   c) NH₂,    -   d) OH,    -   e) NHC₁-C₄alkyl, or    -   f) R₃₁₅;

-   R₃₃₂ is    -   a) H,    -   b) C₁-C₄alkyl,    -   c) OC₁-C₄alkyl,    -   d) SC₁-C₄alkyl, or    -   e) NHC₁-C₄alkyl;

-   R₃₃₃ is    -   a) F, or    -   b) R₃₃₂;

-   R₅₀₀ and R₅₀₃ are each and independently    -   (a) H,    -   (b) halo,    -   (c) C₁-C₈ alkyl,    -   (d) C₃-C₆ cycloalkyl,    -   (e) —(CH₂)_(i)—OR₅₁₁, or    -   (f) —C(═O)—R₅₄₁;

-   R₅₀₁ and R₅₀₂ are each and independently    -   (a) hydrogen atom,    -   (b) C₁-C₈ alkyl,    -   (c) C₁-C₈ alkoxy,    -   (d) C₁-C₈ alkylthio,    -   (e) —(CH₂)_(i)—OR₅₅₁,    -   (f) —O—(CH₂)_(i)—OR₅₅₁,    -   (g) —NR₅₄₂R₅₅₂,    -   (h) —C(═O)—NR₅₄₂R₅₅₂,    -   (i) —(CH₂)_(i)—C(═O)—R₅₄₁,

-   or R₅₀₁ and R₅₀₂ together form    -   (j) ═O,    -   (k) ═NR₅₄₃,    -   (l) ═S,    -   (m) ═CR₅₄₄R₅₅₄, or    -   (n) an unsaturated or saturated 5- or 6-membered hetero ring        having 1-3 hetero atoms selected from the group consisting of a        nitrogen atom, an oxygen atom and a sulfur atom;

-   R₅₁₁ and R₅₁₂ are each and independently    -   (a) hydrogen atom,    -   (b) C₁-C₈ alkyl;

-   R₅₄₁ is    -   (a) hydrogen atom,    -   (b) —(CH₂)_(m)—OH,    -   (c) C₁-C₈ alkyl,    -   (d) C₁-C₈ alkoxy, or    -   (e) —O—CH₂—O—C(═O)—R₅₁₁;

-   R₅₄₂ and R₅₅₂ are each and independently    -   (a) hydrogen atom,    -   (b) —(CH₂)_(i)—OH,    -   (c) C₁-C₈ alkyl,    -   (d) —C(═O)—R₅₄₁,    -   (e) —C(═O)—NR₅₁₁R₅₁₂,    -   (f) —(CH₂)_(q)-phenyl, or        or R₅₄₂ and R₅₅₂ together form a pyrrolidino group, a piperidino        group, a piperazino group, a morpholino group, or a        thiomorpholino group, each of which may be substituted by C₁-C₈        alkyl or —(CH₂)_(i)—OH;

-   R₅₄₃ is    -   (a) H,    -   (b) —OR₅₅₁,    -   (c) C₁-C₈ alkyl,    -   (d) C₁-C₈ alkoxy,    -   (e) —(CH₂)_(q)-phenyl,    -   (f) —NR₅₄₂R₅₅₂,    -   (g) —NH—C(═NH)—NH₂, or    -   (h) [1,2,4]triazol-4-yl;

-   R₅₄₄ and R₅₅₄ are each and independently    -   (a) H,    -   (b) C₁-C₈ alkyl,    -   (c) —C(═O)—R₅₄₁, or    -   (d) —(CH₂)_(q)-phenyl;

-   R₅₅₁ is    -   (a) H,    -   (b) C₁-C₈ alkyl,    -   (c) C₁-C₈ alkyl substituted with 1-3 halo,    -   (d) —(CH₂)_(i)—OR₅₁₁,    -   (e) —(CH₂)_(i)—C(═O)—R₅₄₁, or    -   (f) —C(═O)—(CH₂)_(i)—OR₅₄₄;

-   R₆₀₀ is    -   a) H,    -   b) C₁-C₄alkyl    -   c) het,    -   d) (CH₂)_(b)C(O)OC₁-C₄alkyl,    -   e) (CH₂)_(b)C(O)C₁-C₄alkyl, or    -   f) aryl;

-   R₆₀₁ and R₆₀₂ are each independently    -   a) H,    -   b) C₁-C₄alkyl,    -   c) het,    -   d) C₃-C₆cycloalkyl,    -   e) aryl,    -   f) OC₁-C₄alkyl,    -   g) C(O)OC₁-C₄alkyl; or    -   h) R₆₀₁ and R₆₀₂ taken together along with the carbon atom to        which they attach form a C₃-C₆cycloalkyl;

-   Each R₇₀₀, R₇₀₁, R₇₀₂, R₇₀₃, R₇₀₄, and R₇₀₅ is independently    selected from    -   a) H,    -   b) C₁₋₄ alkyl optionally substituted with 1-3 halo, ═O, ═S, —OH    -   c) C(O)NH₂,    -   d) —CN,    -   e) aryl,    -   f) substituted aryl,    -   g) het,    -   h) substituted het,    -   i) C(O)OH,    -   j) C(O)OC₁₋₄ alkyl, or    -   k) R₇₀₀ and R₇₀₁ form ═O or ═S, or    -   l) R₇₀₂ and R₇₀₃ form ═O or ═S, or    -   m) R₇₀₄ and R₇₀₅ form ═O or ═S;

-   a is 1 or 2;

-   b is 0 or 1;

-   h is 1, 2, or 3;

-   i is 0, 1, or 2;

-   j is 0 or 1;

-   k is 3, 4, or 5;

-   l is 2 or 3;

-   m is 2, 3, 4 or 5;

-   n is 0, 1, 2, 3, 4, or 5;

-   p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are    1, 2, 3, 4, or 5;

-   q is 1, 2, 3, or 4;

-   t is 0, 1, 2, 3, 4, 5, or 6; and

-   w is 0, 1, 2, or 3.

Embodiments of this aspect of the invention may include one or more ofthe following features. 21. R₂ is independently selected from H, F, Cl,Br, CN, NH₂, NO₂, CF₃, and CH₃. The structure of A is

The structure of A is

R₁ is H, —NH₂, —OH, C₁₋₄alkyl, C₃₋₅ cycloalkyl, C₁₋₄ alkoxy, or C₂₋₄alkenyl, the alkyl and alkoxy each optionally being substituted with oneor more halo, —OH, —CN. R₁ is H, —OH, —CH₂—CH═CH₂, methyl, ethyl,propyl, —CH₂—CH₂F, —CH₂—CH₂OH, or methoxy. B is

B is selected from

B and one R₂ form

B and one R₂ form —S—C(O)—N(R₃₀₀)—, —O—C(O)—N(R₃₀₀),—N(R₁₀₆)—HCR₃₀—CH₂—C, —NR₃₀₀—C(O)—C(R₃₂₇R₃₂₈)—O—,—NR₃₀₀—C(O)—C(R₃₂₇R₃₂₈)—S—, —NR₃₀₀—C(S)—C(R₃₂₇R₃₂₈)—S—,—NR₃₀₀—C(O)—C(R₃₂₇R₃₂₈)—CH₂—, —CH₂—CH₂—NR₁₀₇—CH₂—CH₂—, or—CH₂—NR₁₀₇—CH₂—CH₂—CH₂—. D₁ is S. D₁ is O. R₃₀₀ is C₁₋₄ alkyl such asmethyl, ethyl, or isopropyl. One R₂ is hydrogen and the other R₂ is F.Both R₂ substituents are F.

Other aspects of the invention include pharmaceutical compositionsincluding a compound of formulae I, II, or III and a pharmaceuticallyacceptable carrier, and methods for treating microbial infections inmammals by administering an effective amount of a compound of formulaeI, II, or III. The compound may be administered to the mammal orally,parenterally, transdermally, or topically in a pharmaceuticalcomposition. The compound may be administered in an amount of from about0.1 to about 100 mg/kg of body weight/day, such as in an amount of fromabout 1 to about 50 mg/kg of body weight/day.

Specific compounds of the invention include but are not limited to thefollowing.

-   (5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-methyl-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-allyl-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-propyl-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-methoxy-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-hydroxy-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3,5-Difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[4-(3-Pyridyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[4-(4-Pyridyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[4-(3,6-Dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[4-(Tetrahydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide    S-oxide;-   (5R)-(−)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-(−)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-3-[3-Fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3-Fluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-3-[4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-3-[3,5-Difluoro-4-(Tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-(−)-3-[3,5-Difluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3,5-Difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3,5-difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(cis-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(cis-1-imino-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(cis-1-Imino-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(cis-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran    -4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(trans-1-(imino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(trans-1-(imino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(trans-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(trans-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-N-methyl-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-N-Methyl-3-[3-fluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[4-(Thiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-(−)-3-[4-(Thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-(−)-3-[3-Fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-(−)-3-[3-Fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S-oxide;-   (5R)-3-[3-Fluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3-Fluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3-Fluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3-Fluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3,5-Difluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3,5-Difluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3,5-Difluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3,5-Difluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3,5-Difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S-oxide;-   (5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S-oxide;-   (5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide;-   (5R)-(−)-3-(2,3-Dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-(2,3-Dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-(2,3-Dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Ethyl-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-(2-Hydroxyethyl)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-(2-Fluoroethyl)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2,3-Dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2,3-Dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2,3-Dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-(2,3-Dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-(2,3-Dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2,3-Dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[(2R)-2,3-Dihydro-1-formyl-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[(2R)-2,3-Dihydro-1-(hydroxyacetyl)-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-3-[3,5-Difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3,5-Difluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3,5-difluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3-Fluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3-fluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(3,4-Dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-(2-Fluoroethyl)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(3,4-Dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2,2-Difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(4-Methyl-3-thioxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(3,4-dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(3,4-dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3-Fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(2,5-Dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(4-Oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Ethyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(4-Oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Ethyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-(2-Fluoroethyl)-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(4-Oxo-3,4-dihydro-1(2H)-pyridinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Ethyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3,5-difluorophenyl]-2-oxo    -5-oxazolidinecarboxamide;-   (5R)-3-[4-[3,4-Dihydro-4-(hydroxyimino)-1(2H)-pyridinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(2-Formyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(2-formyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[2-(Hydroxyacetyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[2-(hydroxyacetyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-(3-Formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-(3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[3-(Hydroxyacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[3-(hydroxyacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(1-(2(S)-Hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)    -3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(1-(2(S)-hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(1-(2(S),3-Dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)    -3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(1-(2(S)-Hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-N-Methyl-3-[4-(1-(2(S)-hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;-   (5R)-3-[4-(1-(2(S),3-Dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;    and-   (5R)-N-Methyl-3-[4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide.

DETAILED DESCRIPTION OF THE DRAWINGS

FIGS. I-V illustrate exemplary procedures for producingpyridine/pyrimidine-phenyl oxazolidinonecarboxamides of the invention.

FIGS. VI-IX illustrate exemplary procedures for producingtetrahydropyridyl/thiopyranyl/pyranyl-phenyl oxazolidinonecarboxamidesof the invention.

FIGS. X-XV illustrate exemplary procedures for producingbenzooxazolyl/benzthiazolyl-phenyl oxazolidinonecarboxamides of theinvention.

FIGS. XVI-XVII illustrate exemplary procedures for producingfluorenyl/phenanthrenyl/pyrido[1,2-a]quinolinyl-phenyloxazolidinonecarboxamides of the invention.

FIG. XVIII illustrates an exemplary procedure for producingbicyclo[3.1.0]hexyl-phenyl oxazolidinonecarboxamides of the invention.

FIGS. XIX-XXVI illustrate exemplary procedures for producingbenzo[e]azulenyl-phenyl oxazolidinonecarboxamides of the invention.

FIGS. XXVII-XXVIII illustrate exemplary procedures for producingoxo-benzooxazolyl/oxo-benzothiazolyl-phenyl oxazolidinonecarboxamides ofthe invention.

FIGS. XXIX-XXIX illustrate exemplary procedures for producingbenzooxazinyl/benzothiazinyl-phenyl oxazolidinonecarboxamides of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described.

Variables including a letter followed by a numeric superscript areequivalent to the same letter followed by the same number as asubscript. For instance, R¹ and R₁ are equivalent and refer to the samevariable.

The carbon atom content of various hydrocarbon-containing moieties maybe indicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i-j) indicates a moietyof the integer “i” to the integer “j” carbon atoms, inclusive. Thus, forexample, C₁₋₇ alkyl refers to alkyl of one to seven carbon atoms,inclusive.

The term “halo” refers to a halogen atom selected from Cl, Br, I, and F.

The term “alkyl” refers to both straight- and branched-chain moieties.Unless otherwise specifically stated, such as by a C_(i-j) prefix, alkylmoieties include between 1 and 6 carbon atoms.

The term “alkenyl” refers to both straight- and branched-chain moietiescontaining at least one —C═C—. Unless otherwise specifically stated,such as by a C_(i-j) prefix, alkenyl moieties include between 2 and 6carbon atoms.

The term “alkynyl” refers to both straight- and branched-chain moietiescontaining at least one —C≡C—. Unless otherwise specifically stated,such as by a C_(i-j) prefix, alkynyl moieties include between 2 and 6carbon atoms.

The term “alkoxy” refers to —O-alkyl groups. Unless otherwisespecifically stated, such as by a C_(i-j) prefix, the alkyl portion ofthe —O-alkyl group includes between 1 and 6 carbon atoms.

The term “amino” refers to NH₂.

The term “cycloalkyl” refers to a cyclic alkyl moiety. Unless otherwisespecifically stated, such as by a C_(i-j) prefix, cycloalkyl moietieswill include between 3 and 7 carbon atoms.

The term “cycloalkenyl” refers to a cyclic alkenyl moiety. Unlessotherwise specifically stated, such as by a C_(i-j) prefix, cycloalkenylmoieties will include between 3 and 7 carbon atoms and at least one—C═C— group within the cyclic ring.

The term “aryl” refers to phenyl and naphthyl.

The term “het” refers to mono- or bicyclic ring systems containing atleast one heteroatom selected from O, S, and N. Each monocyclic ring maybe aromatic, saturated, or partially unsaturated. A bicyclic ring systemmay include a monocyclic ring containing at least one heteroatom whichis fused with a cycloalkyl or aryl group. A bicyclic ring system mayalso include a monocyclic ring containing at least one heteroatom fusedwith another het, monocyclic ring system.

Examples of “het” include, but are not limited to, pyridine, thiophene,furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl,4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl,5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl,3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl,4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl,2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl,5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole,1,2,4-dithiazolone, phthalimide, quinolinyl, morpholinyl, benzoxazoyl,diazinyl, triazinyl, quinolinyl, quinoxalinyl, naphthyridinyl,azetidinyl, pyrrolidinyl, hydantoinyl, oxathiolanyl, dioxolanyl,imidazolidinyl, and azabicyclo[2.2.1]heptyl.

The term “heteroaryl” refers to an aromatic het, examples of whichinclude, but are not limited to, pyridine and thiophene.

The term “substituted alkyl” refers to an alkyl moiety including 1-4substituents selected from halo, het, cycloalkyl, cycloalkenyl, aryl,—OQ₁₀, —SQ₁₀, —S(O)₂Q₁₀, —S(O)Q₁₀, —OS(O)₂Q₁₀, —C(═NQ₁₀)Q₁₀,—C(═NOH)Q₁₀, —SC(O)Q₁₀, —NQ₁₀Q₁₀, —C(O)Q₁₀, —C(S)Q₁₀, —C(O)OQ₁₀,—OC(O)Q₁₀, —C(O)NQ₁₀Q₁₀, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN, ═O, ═S,—NQ₁₀C(O)Q₁₀, —NQ₁₀C(O)NQ₁₀Q₁₀, —S(O)₂NQ₁₀Q₁₀, —NQ₁₀S(O)₂Q₁₀,—NQ₁₀S(O)Q₁₀, —NQ₁₀SQ₁₀, —NO₂, —OPO(OH)₂, and —SNQ₁₀Q₁₀. Each of thehet, cycloalkyl, cycloalkenyl, and aryl may be optionally substitutedwith 1-4 substituents independently selected from halo and Q₁₅.

The term “substituted aryl” refers to an aryl moiety having 1-3substituents selected from —OQ₁₀, —SQ₁₀, —S(O)₂Q₁₀, —S(O)Q₁₀,—OS(O)₂Q₁₀, —C(═NQ₁₀)Q₁₀, —C(═NOH)Q₁₀, —SC(O)Q₁₀, —NQ₁₀Q₁₀, —C(O)Q₁₀,—C(S)Q₁₀, —C(O)OQ₁₀, —OC(O)Q₁₀, —C(O)NQ₁₀Q₁₀, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN,—NQ₁₀C(O)Q₁₀, —NQ₁₀C(O)NQ₁₀Q₁₀, —S(O)₂NQ₁₀Q₁₀, —NQ₁₀S(O)₂Q₁₀,—NQ₁₀S(O)Q₁₀, —NQ₁₀SQ₁₀, —NO₂, —SNQ₁₀Q₁₀, alkyl, substituted alkyl, het,halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl,cycloalkenyl, and aryl may be optionally substituted with 1-3substituents selected from halo and Q₁₅.

The term “substituted het” refers to a het moiety including 1-4substituents selected from —OQ₁₀, —SQ₁₀, —S(O)₂Q₁₀, —S(O)Q₁₀,—OS(O)₂Q₁₀, —C(═NQ₁₀)Q₁₀, —C(═NOH)Q₁₀, —SC(O)Q₁₀, —NQ₁₀Q₁₀, —C(O)Q₁₀,—C(S)Q₁₀, —C(O)OQ₁₀, —OC(O)Q₁₀, —C(O)NQ₁₀Q₁₀, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN,—NQ₁₀C(O)Q₁₀, —NQ₁₀C(O)NQ₁₀Q₁₀, —S(O)₂NQ₁₀Q₁₀, —NQ₁₀S(O)₂Q₁₀,—NQ₁₀S(O)Q₁₀, —NQ₁₀SQ₁₀, —NO₂, —SNQ₁₀Q₁₀, alkyl, substituted alkyl, het,halo, cycloalkyl, cycloalkenyl, and aryl. The substituted het also maybe substituted by one or more ═O or ═S substituents provided that the Oor S are bound to ring atoms capable of supporting a double bond betweenthe ring atom and O or S. The het, cycloalkyl, cycloalkenyl, and arylmay be optionally substituted with 1-3 substituents selected from haloand Q₁₅.

The term “substituted alkenyl” refers to a alkenyl moiety including 1-3substituents —OQ₁₀, —SQ₁₀, —S(O)₂Q₁₀, —S(O)Q₁₀, —OS(O)₂Q₁₀,—C(═NQ₁₀)Q₁₀, —SC(O)Q₁₀, —NQ₁₀Q₁₀, —C(O)Q₁₀, —C(S)Q₁₀, —C(O)OQ₁₀,—OC(O)Q₁₀, —C(O)NQ₁₀Q₁₀, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN, ═O, ═S,—NQ₁₀C(O)Q₁₀, —NQ₁₀C(O)NQ₁₀Q₁₀, —S(O)₂NQ₁₀Q₁₀, —NQ₁₀S(O)₂Q₁₀,—NQ₁₀S(O)Q₁₀, —NQ₁₀SQ₁₀, —NO₂, —SNQ₁₀Q₁₀, alkyl, substituted alkyl, het,halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl,cycloalkenyl, and aryl may be optionally substituted with 1-3substituents selected from halo and Q₁₅.

The term “substituted alkoxy” refers to an alkoxy moiety including 1-3substituents —OQ₁₀, —SQ₁₀, —S(O)₂Q₁₀, —S(O)Q₁₀, —OS(O)₂Q₁₀,—C(═NQ₁₀)Q₁₀, —SC(O)Q₁₀, —NQ₁₀Q₁₀, —C(O)Q₁₀, —C(S)Q₁₀, —C(O)OQ₁₀,—OC(O)Q₁₀, —C(O)NQ₁₀Q₁₀, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN, ═O, ═S,—NQ₁₀C(O)Q₁₀, —NQ₁₀C(O)NQ₁₀Q₁₀, —S(O)₂NQ₁₀Q₁₀, —NQ₁₀S(O)₂Q₁₀,—NQ₁₀S(O)Q₁₀, —NQ₁₀SQ₁₀, —NO₂, —SNQ₁₀Q₁₀, alkyl, substituted alkyl, het,halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl,cycloalkenyl, and aryl may be optionally substituted with 1-3substituents selected from halo and Q₁₅.

The term “substituted cycloalkenyl” refers to a cycloalkenyl moietyincluding 1-3 substituents —OQ₁₀, —SQ₁₀, —S(O)₂Q₁₀, —S(O)Q₁₀,—OS(O)₂Q₁₀, —C(═NQ₁₀)Q₁₀, —SC(O)Q₁₀, —NQ₁₀Q₁₀, —C(O)Q₁₀, —C(S)Q₁₀,—C(O)OQ₁₀, —OC(O)Q₁₀, —C(O)NQ₁₀Q₁₀, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN, ═O, ═S,—NQ₁₀C(O)Q₁₀, —NQ₁₀C(O)NQ₁₀Q₁₀, —S(O)₂NQ₁₀Q₁₀, —NQ₁₀S(O)₂Q₁₀,—NQ₁₀S(O)Q₁₀, —NQ₁₀SQ₁₀, —NO₂, —SNQ₁₀Q₁₀, alkyl, substituted alkyl, het,halo, cycloalkyl, cycloalkenyl, and aryl. The het, cycloalkyl,cycloalkenyl, and aryl may be optionally substituted with 1-3substituents selected from halo and Q₁₅.

The term “substituted amino” refers to an amino moiety in which one orboth of the amino hydrogens are replaced with a group selected from—OQ₁₀, —SQ₁₀, —S(O)₂Q₁₀, —S(O)Q₁₀, —OS(O)₂Q₁₀, —C(O)Q₁₀, —C(S)Q₁₀,—C(O)OQ₁₀, —OC(O)Q₁₀, —C(O)NQ₁₀Q₁₀, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN, alkyl,substituted alkyl, het, halo, cycloalkyl, cycloalkenyl, and aryl. Thehet, cycloalkyl, cycloalkenyl, and aryl may be optionally substitutedwith 1-3 substituents selected from halo and Q₁₅.

Each Q₁₀ is independently selected from —H, alkyl, cycloalkyl, het,cycloalkenyl, and aryl. The het, cycloalkyl, cycloalkenyl, and aryl maybe optionally substituted with 1-3 substituents selected from halo andQ₁₃.

Each Q₁₁ is independently selected from —H, halo, alkyl, aryl,cycloalkyl, and het. The alkyl, cycloalkyl, and het may be optionallysubstituted with 1-3 substituents independently selected from halo,—NO₂, —CN, ═S, ═O, and Q₁₄. The aryl may be optionally substituted with1-3 substituents independently selected from halo, —NO₂, —CN, and Q₁₄.

Each Q₁₃ is independently selected from Q₁₁, —OQ₁₁, —SQ₁₁, —S(O)₂Q₁₁,—S(O)Q₁₁, —OS(O)₂Q₁₁, —C(═NQ₁₁)Q₁₁, —SC(O)Q₁₁, —NQ₁₁Q₁₁, —C(O)Q₁₁,—C(S)Q₁₁, —C(O)OQ₁₁, —OC(O)Q₁₁, —C(O)NQ₁₁Q₁₁, —C(O)C(Q₁₆)₂OC(O)Q₁₀, —CN,═O, ═S, —NQ₁₁C(O)Q₁₁, —NQ₁₁C(O)NQ₁₁Q₁₁, —S(O)₂NQ₁₁Q₁₁, —NQ₁₁S(O)₂Q₁₁,—NQ₁₁S(O)Q₁₁, —NQ₁₁SQ₁₁, —NO₂, and —SNQ₁₁Q₁₁, provided that Q₁₃ is not═O or ═S when Q₁₀ is aryl or a het lacking any atom capable of forming adouble bond with O or S.

Each Q₁₄ is —H or a substituent selected from alkyl, cycloalkyl,cycloalkenyl, phenyl, or naphthyl, each optionally substituted with 1-4substituents independently selected from —F, —Cl, —Br, —I, —OQ₁₆, —SQ₁₆,—S(O)₂Q₁₆, —S(O)Q₁₆, —OS(O)₂Q₁₆, —NQ)₆Q₁₆, —C(O)Q₁₆, —C(S)Q₁₆,—C(O)OQ₁₆, —NO₂, —C(O)NQ₁₆Q₁₆, —CN, —NQ₁₆C(O)Q₁₆, —NQ₁₆C(O)NQ₁₆Q₁₆,—S(O)₂NQ₁₆Q₁₆, and —NQ₁₆S(O)₂Q₁₆. The alkyl, cycloalkyl, andcycloalkenyl may be further substituted with ═O or ═S.

Each Q₁₅ is alkyl, cycloalkyl, cycloalkenyl, het, phenyl, or naphthyl,each optionally substituted with 1-4 substituents independently selectedfrom —F, —Cl, —Br, —I, —OQ₁₆, —SQ₁₆, —S(O)₂Q₁₆, —S(O)Q₁₆, —OS(O)₂Q₁₆,—C(═NQ₁₆)Q₁₆, —SC(O)Q₁₆, —NQ₁₆Q₁₆, —C(O)Q₁₆, —C(S)Q₁₆, —C(O)OQ₁₆,—OC(O)Q₁₆, —C(O)NQ₁₆Q₁₆, —C(O)C(Q₁₆)₂OC(O)Q₁₆, —CN, —NQ₁₆C(O)Q₁₆,—NQ₁₆C(O)NQ₁₆Q₁₆, —S(O)₂NQ₁₆Q₁₆, —NQ₁₆S(O)₂Q₁₆, —NQ₁₆S(O)Q₁₆, —NQ₁₆SQ₁₆,—NO₂, and —SNQ₁₆Q₁₆. The alkyl, cycloalkyl, and cycloalkenyl may befurther substituted with ═O or ═S.

Each Q₁₆ is independently selected from —H, alkyl, and cycloalkyl. Thealkyl and cycloalkyl may optionally include 1-3 halos.

Specific R₂ substituents include H, F, Cl, Br, —CN, —NH₂, —NO₂, —CH₃.

Specific structures of A include

Mammal refers to human or animals.

The compounds of the present invention are generally named according tothe IUPAC or CAS nomenclature system. Abbreviations which are well knownto one of ordinary skill in the art may be used (e.g. “Ph” for phenyl,“Me” for methyl, “Et” for ethyl, “0” for oxygen atom, “S” for sulfuratom, “N” for nitrogen atom, “h” for hour or hours and “rt” for roomtemperature).

It is to be understood that the present invention encompasses anyracemic, optically-active, polymorphic, tautomeric, or stereoisomericform, or mixture thereof, of a compound of the invention which possessesthe useful properties described herein.

The compounds of the present invention can be converted to their salts,where appropriate, according to conventional methods.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, use of the compounds as pharmaceuticallyacceptable salts may be appropriate. Examples of pharmaceuticallyacceptable salts which are within the scope of the present inventioninclude organic acid addition salts formed with acids which form aphysiological acceptable anion and inorganic salts. Examples ofpharmaceutically acceptable salts include, but are not limited to, thefollowing acids: acetic, aspartic, benzenesulfonic, benzoic, bicarbonic,bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic,chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic,fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic,hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic,hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic,malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic,muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic,pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric,phthalic, polygalactouronic, propionic, salicylic, stearic, succinic,sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic andtoluenesulfonic. Examples of pharmaceutically acceptable salts include,but are not limited to, the following bases: primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, and thelike. The pharmaceutically acceptable salts may be in hydrated form.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The compounds of Formula I of this invention contain a chiral center,such as at C-5 of the oxazolidinone ring, and as such there exist twoenantiomers or a racemic mixture of both. This invention relates to boththe enantiomer that possesses the useful properties described herein, aswell as to mixtures containing both of the isomers. In addition,depending on substituents, additional chiral centers and other isomericforms may be present in any of A, B, or R₁ groups, and this inventionembraces all possible stereoisomers and geometric forms in these groups.

The compounds of this invention are useful for treatment of microbialinfections in humans and other warm blooded animals.

Dosages and Pharmaceutical Compositions

By the phrase “effective amount” of a compound as provided herein ismeant a nontoxic but sufficient amount of one or more compounds of thisinvention to provide the desired effect. The desired effect may be toprevent, give relief from, or ameliorate microbial infections.

As pointed out below, the exact amount of the compound of this inventionrequired to treat a microbial infection will vary from subject tosubject, depending on the species, age, and general condition of thesubject, the severity of the disease that is being treated, theparticular compound(s) used, and the mode of administration, such as theroute and frequency of administration, and the like. Thus, it is notpossible to specify an exact “effective amount.” However, an appropriateeffective amount may be determined by one of ordinary skill in the artusing only routine experimentation.

Pharmaceutical compositions of this invention may be prepared bycombining the compounds of this invention with a solid or liquidpharmaceutically acceptable carrier and, optionally, withpharmaceutically acceptable adjuvants and excipients employing standardand conventional techniques. Solid form compositions include powders,tablets, dispersible granules, capsules, cachets and suppositories. Asolid carrier can be at least one substance which may also function as adiluent, flavoring agent, solubilizer, lubricant, suspending agent,binder, tablet disintegrating agent, and encapsulating agent. Inertsolid carriers include magnesium carbonate, magnesium stearate, talc,sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials,low melting wax, cocoa butter, and the like. Liquid form compositionsinclude solutions, suspensions and emulsions. For example, there may beprovided solutions of the compounds of this invention dissolved in waterand water-propylene glycol systems, optionally containing suitableconventional coloring agents, flavoring agents, stabilizers andthickening agents.

Preferably, the pharmaceutical composition is provided employingconventional techniques in unit dosage form containing effective orappropriate amounts of the active component, that is, the compoundaccording to this invention.

The quantity of active component, that is the compound according to thisinvention, in the pharmaceutical composition and unit dosage formthereof may be varied or adjusted widely depending upon the particularapplication, the potency of the particular compound and the desiredconcentration. Generally, the quantity of active component will rangebetween 0.5% to 90% by weight of the composition.

In therapeutic use for treating, or combating, bacterial infections inwarm-blooded animals, the compounds or pharmaceutical compositionsthereof will be administered orally, parenterally and/or topically at adosage to obtain and maintain a concentration, that is, an amount, orblood-level of active component in the animal undergoing treatment whichwill be antibacterially effective. Generally, such antibacteriallyeffective amount of dosage of active component will be in the range ofabout 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg ofbody weight/day. It is to be understood that the dosages may varydepending upon the requirements of the patient, the severity of thebacterial infection being treated, and the particular compound beingused. Also, it is to be understood that the initial dosage administeredmay be increased beyond the above upper level in order to rapidlyachieve the desired blood-level or the initial dosage may be smallerthan the optimum and the daily dosage may be progressively increasedduring the course of treatment depending on the particular situation. Ifdesired, the daily dose may also be divided into multiple doses foradministration, e.g., 2-4 times per day.

A specific active agent may have more than one recommended dosage range,particularly for different routes of administration. Generally, aneffective amount of dosage of compounds of this invention, eitheradministered individually or in combination with other inhibitorcompound(s), will be in the range of about 5 to about 2500 mg/day, morespecifically about 10 to about 750 mg/day, and most conveniently from 50to 500 mg per unit dosage form. It is to be understood that the dosagesof active component(s) may vary depending upon the requirements of eachsubject being treated and the severity of the microbial infection.

Initial treatment of a patient suffering from microbial infection canbegin with a dosage regimen as indicated above. Treatment is generallycontinued as necessary over a period of several days to several monthsuntil the condition or disorder has been controlled or eliminated.Patients undergoing treatment with a composition of the invention can beroutinely monitored by any of the methods well known in the art todetermine the effectiveness of therapy. Continuous analysis of data fromsuch monitoring permits modification of the treatment regimen duringtherapy so that optimally effective amounts of drug are administered atany point in time, and so that the duration of treatment can bedetermined. In this way, the treatment regimen and dosing schedule canbe rationally modified over the course of therapy so that the lowestamount of the compounds of this invention exhibiting satisfactoryeffectiveness is administered, and so that administration is continuedonly for so long as is necessary to successfully treat the condition ordisorder.

In a combination therapy, the compound(s) of this invention and otherinhibitor compound(s) can be administered simultaneously or at separateintervals. When administered simultaneously the compound(s) of thisinvention and the other inhibitor compound(s) can be incorporated into asingle pharmaceutical composition or into separate compositions, e.g.,compound(s) of this invention in one composition and the other inhibitorcompound(s) in another composition. For instance, the compound(s) ofthis invention may be administered concurrently or concomitantly withthe other inhibitor compound(s). The term “concurrently” means thesubject being treated takes one drug within about 5 minutes of takingthe other drug. The term “concomitantly” means the subject being treatedtakes one drug within the same treatment period of taking the otherdrug. The same treatment period is preferably within twelve hours and upto forty-eight hours.

When separately administered, therapeutically effective amounts ofcompound(s) of this invention and the other inhibitor compound(s) areadministered on a different schedule. One may be administered before theother as long as the time between the two administrations falls within atherapeutically effective interval. A therapeutically effective intervalis a period of time beginning when one of either (a) the compound(s) ofthis invention, or (b) the other inhibitor compound(s) is administeredto a mammal and ending at the limit of the beneficial effect in thetreatment of microbial infections of the combination of (a) and (b). Themethods of administration of the compound(s) of this invention and theother inhibitor compound(s) may vary. Thus, one agent may beadministered orally, while the other is administered by injection.

In addition to the compounds of this invention and other antimicrobialagents, the pharmaceutical composition for therapeutic use may alsocomprise one or more non-toxic, pharmaceutically acceptable carriermaterials or excipients. The term “carrier” material or “excipient”herein means any substance, not itself a therapeutic agent, used as acarrier and/or diluent and/or adjuvant, or vehicle for delivery of atherapeutic agent to a subject or added to a pharmaceutical compositionto improve its handling or storage properties or to permit or facilitateformation of a dose unit of the composition into a discrete article suchas a capsule or tablet suitable for oral administration. Excipients caninclude, by way of illustration and not limitation, diluents,disintegrants, binding agents, adhesives, wetting agents, polymers,lubricants, glidants, substances added to mask or counteract adisagreeable taste or odor, flavors, dyes, fragrances, and substancesadded to improve appearance of the composition. Acceptable excipientsinclude lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropyl-methyl cellulose, or other methodsknown to those skilled in the art. For oral administration, thepharmaceutical composition may be in the form of, for example, a tablet,capsule, suspension or liquid. If desired, other active ingredients maybe included in the composition.

Routes of Administration

In therapeutic use for treating, or combating, infections in a mammal(i.e., humans and animals) the pharmaceutical composition can beadministered orally, parenterally, topically, rectally, or intranasally.

In addition to the oral dosing, noted above, the compositions of thepresent invention may be administered by any suitable route, in the formof a pharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compositions may, for example,be administered parenterally, e.g., intravascularly, intraperitoneally,subcutaneously, or intramuscularly. For parenteral administration,saline solution, dextrose solution, or water may be used as a suitablecarrier. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

Generally, the concentration of each of the compounds of this inventionin a liquid composition, such as a lotion, will be from about 0.1 wt. %to about 20 wt. %, preferably from about 0.5 wt. % to about 10 wt. %.The solution may contain other ingredients, such as emulsifiers,antioxidants or buffers. The concentration in a semi-solid or solidcomposition, such as a gel or a powder, will be about 0.1 wt. % to about5 wt. %, preferably about 0.5 wt. % to about 2.5 wt. %. When topicallydelivered, the pharmaceutical composition of the present invention beingutilized to effect targeted treatment of a specific internal site, eachof the compounds of this invention is preferably contained in thecomposition in an amount of from 0.05-10 wt. %, more preferably 0.5-5wt. %.

Parenteral administrations include injections to generate a systemiceffect or injections directly to the afflicted area. Examples ofparenteral administrations are subcutaneous, intravenous, intramuscular,intradermal, intrathecal, intraocular, intravetricular, and generalinfusion techniques.

Topical administrations include the treatment of infectious areas ororgans readily accessibly by local application, such as, for example,eyes, ears including external and middle ear infections, vaginal, openand sutured or closed wounds and skin. It also includes transdermaldelivery to generate a systemic effect.

The rectal administration includes the form of suppositories.

The intranasally administration includes nasal aerosol or inhalationapplications.

Pharmaceutical compositions including the compounds of this inventionmay be prepared by methods well known in the art, e.g., by means ofconventional mixing, dissolving, granulation, dragee-making, levigating,emulsifying, encapsulating, entrapping, lyophilizing processes or spraydrying.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries that facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For oral administration, the compounds of this invention can beformulated by combining the active compounds with pharmaceuticallyacceptable carriers well known in the art. Such carriers enable thecompounds of the invention to be formulated as tablets, pills, lozenges,dragees, capsules, liquids, solutions, emulsions, gels, syrups,slurries, suspensions and the like, for oral ingestion by a patient. Acarrier can be at least one substance which may also function as adiluent, flavoring agent, solubilizer, lubricant, suspending agent,binder, tablet disintegrating agent, and encapsulating agent. Examplesof such carriers or excipients include, but are not limited to,magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose,pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosicmaterials, low melting wax, cocoa butter or powder, polymers such aspolyethylene glycols and other pharmaceutical acceptable materials.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identificatin or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, liquid polyethyleneglycols, cremophor, capmul, medium or long chain mono-, di- ortriglycerides. Stabilizers may also be added in these formulations.

Liquid form compositions include solutions, suspensions and emulsions.For example, there may be provided solutions of pharmaceuticalcompositions with the compounds of this invention dissolved in water andwater-propylene glycol and water-polyethylene glycol systems, optionallycontaining suitable conventional coloring agents, flavoring agents,stabilizers and thickening agents.

The compounds of this invention may also be formulated for parenteraladministration, e.g., by injections, bolus injection or continuousinfusion. Formulations for parenteral administration may be presented inunit dosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulating materials such as suspending, stabilizing and/or dispersingagents.

For injection, the compounds of this invention may be formulated inaqueous solution, preferably in physiologically compatible buffers orphysiological saline buffer. Suitable buffering agents includetri-sodium orthophosphate, sodium bicarbonate, sodium citrate,N-methyl-glucamine, L(+)-lysine and L(+)-arginine.

The compositions can also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

Other parenteral administrations also include aqueous solutions of awater soluble form, such as, without limitation, a salt, of thecompounds of this invention. Additionally, suspensions of the activecompounds may be prepared in a lipophilic vehicle. Suitable lipophilicvehicles include fatty oils such as sesame oil, synthetic fatty acidesters such as ethyl oleate and triglycerides, or materials such asliposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers and/or agents that increase the solubilityof the compounds to allow for the preparation of highly concentratedsolutions.

Alternatively, the compounds of this invention may be in a powder formfor constitution with a suitable vehicle (e.g., sterile, pyrogen-freewater) before use.

For suppository administration, the pharmaceutical compositions may alsobe formulated by mixing the compounds of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat rectal temperature and therefore will melt in the rectum to releasethe drug. Such materials include cocoa butter, beeswax and otherglycerides.

For administration by inhalation, the compounds of this invention can beconveniently delivered through an aerosol spray in the form of solution,dry powder, or cream. The aerosol may use a pressurized pack or anebulizer and a suitable propellant. In the case of a pressurizedaerosol, the dosage unit may be controlled by providing a valve todeliver a metered amount. Capsules and cartridges of, for example,gelatin for use in an inhaler may be formulated containing a power basesuch as lactose or starch.

For ophthalmic and otitis uses, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative, such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment, such as petrolatum.

In addition to the formulations described previously, the compounds ofthis invention may also be formulated as depot preparations. Such longacting formulations may be in the form of implants. The compounds ofthis invention may be formulated for this route of administration withsuitable polymers, hydrophobic materials, or as a sparing solublederivative such as, without limitation, a sparingly soluble salt.

Additionally, the compounds of this invention may be delivered using asustained-release system. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for 24 hours up to several days. Depending on thechemical nature and the biological stability of the therapeutic reagent,additional strategies for protein stabilization may be employed. Incertain embodiments, the compounds of this invention are appliedtopically. For topical applications, the pharmaceutical composition maybe formulated in a suitable ointment containing the compounds of thisinvention suspended or dissolved in one or more carriers. Carriers fortopical administration of the compounds of this invention include, butare not limited to, mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene, polyoxypropylene compound,emulsifying wax and water. Alternatively, the pharmaceuticalcompositions can be formulated in a suitable lotion such as suspensions,emulsion, or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, ceteary alcohol,2-octyldodecanol, benzyl alcohol and water.

In some embodiments, the antibacterial compounds are prodrugs of thecompounds of this invention. The expression “prodrug” denotes aderivative of a known direct acting drug, which is transformed into theactive drug by an enzymatic or chemical process. Prodrugs of thecompounds of this invention are prepared by modifying functional groupspresent on the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include, but are not limited to, compounds whereinhydroxy, amine or sulfhydryl groups are bonded to any group that, whenadministered to the animal, cleaves to form the free hydroxyl, amino orsulfhydryl group, respectively. Representative examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups. See Notari, R. E.,“Theory and Practice of Prodrug Kinetics,” Methods in Enzymology,112:309-323 (1985); Bodor, N., “Novel Approaches in Prodrug Design,”Drugs of the Future, 6(3):165-182 (1981); and Bundgaard, H., “Design ofProdrugs: Bioreversible-Derivatives for Various Functional Groups andChemical Entities,” in Design of Prodrugs (H. Bundgaard, ed.), Elsevier,N.Y. (1985).

The antibacterial agents of this invention have useful activity againsta variety of organisms. The in vitro activity of compounds of thisinvention can be assessed by standard testing procedures such as thedetermination of minimum inhibitory concentration (MIC) by agar dilutionas described in “Approved Standard. Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria That Grow Aerobically”, 3rd. ed.,published 1993 by the National Committee for Clinical LaboratoryStandards, Villanova, Pa., USA.

The following Charts describe the preparation of compounds of thepresent invention. The starting materials are prepared by proceduresdescribed in these charts or by procedures known to one of ordinaryskill in the art.

CHART I illustrates methods for preparing aryloxazolidinone-5-carboxamides 5 and their N-substituted derivatives. InMETHOD A, aryl carbamate derivatives 1 (B4=C(1-6)alkyl or benzyl) (knownin the literature, prepared by known methods such as by derivatizing theaniline 6, or described in the charts to follow) can be deprotonatedwith a lithium base such as n-butyllithium in a suitable solvent such asTHF at a suitable temperature, typically in a range of −78° C. to −40°C., to give a lithiated species which is directly treated with potassium(2R)-glycidate (J. Org. Chem. 1992, 57(12), 3380-3387). Warming toambient temperature and stirring for a suitable period of time affordsthe aryl oxazolidinone-5(R)-carboxylic acids 3. The acids 3 can than beconverted to the targeted structures 5 using methods known to thoseskilled in the art. For instance, treatment of the acids 3 with oxalylchloride under an inert atmosphere affords the acid chlorideintermediates which can be converted to the amides 5 (R₁=H or optionallysubstituted alkyl) upon treatment with ammonia or optionally substitutedalkyl amines (R₁NH₂) or to the hydroxamates 5 (R₁=Oalkyl) upon treatmentwith O-alkylhydroxylamines. The hydroxamate derivatives can also beprepared directly from the acids 3 upon treatment with anO-alkylhydroxylamine (or its hydrochloride salt) in the presence of acoupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride. When R₁ is O-benzyl, hydrogenolysis of 5 then affords thehydroxamic acid derivatives (R₁=OH). Alternatively, the acids 3 can beconverted to the targeted structures 5 via the ester intermediates 4(B5=methyl, ethyl, propyl, butyl, for example) using methods known tothose skilled in the art. For example, the methyl esters 4 (B5=Me) canbe prepared by treating methanolic solutions of the acids 3 with an acidcatalyst such as sulfuric acid at ambient temperature. Subsequenttreatment with amines R₁NH₂ in a suitable solvent such as methanol oracetonitrile then affords the amides 5 (R₁=H or optionally substitutedalkyl). Similarly, treatment with hydrazine gives the hydrazides 5(R₁=NH₂).

In METHOD B, (5R)-hydroxymethyl aryl oxazolidinones 2 can be oxidizedusing, for example, chromium(VI) oxide/sulfuric acid in a solvent systemsuch as acetone/water (EP 91-417044, 13 Mar. 1991; Appl. EP 90-810654,29 Aug. 1990) or ruthenium(III) chloride (cat.)/sodium periodate in thepresence of sodium dihydrogenphosphate in a solvent system such asacetonitrile/methylene chloride/water (See U.S. Pat. No. 5,614,535, theentire contents of which are incorporated herein) to give the aryloxazolidinone-5(R)-carboxylic acids 3 which can then be converted to thetargeted structures 5 as described previously. The (5R)-hydroxymethylaryl oxazolidinone starting materials 2 may be obtained by treating thearyl carbamates 1 with a lithium base such as n-butyllithium or lithiumhexamethyldisilazide in a solvent such as THF at a suitable temperature,typically in a range from −78° C. to −40° C., to give a lithiatedspecies which is directly treated with R-(−)-glycidyl butyrate. Warmingto room temperature then affords the structures 2.

In METHOD C, anilines 6, which are known in the literature or producedby known methods (see also the charts to follow), can be converted tostructures 7 upon treatment with an alkyl (2R)-epoxypropanoate andlithium triflate in a suitable solvent such as acetonitrile at asuitable temperature, typically in a range from 20° C. to 110° C.depending on the solvent. Amino alcohols 7 can then be ring closed togive the aryl oxazolidinones 4 using methods known to one skilled in theart. For instance, treatment of structures 7 with1,1′-carbonyldiimidazole in a solvent such as acetonitrile or THF at anappropriate temperature, typically in a range of 20° C. to 60° C., orwith phosgene in a solvent such as toluene or methylene chloride, ormixtures thereof, in the presence of a base such as triethylamine at anappropriate temperature, typically in a range from −10° C. to 25° C.,affords the oxazolidinones 4. The structures 4 can then be converted tothe targeted compounds 5 using the methods described previously.

CHART II illustrates a preparation of the thiopyran-4-yl phenyloxazolidinone-5-carboxamides 10 and 11. The(3,6-dihydro-2H-thiopyran-4-yl)phenyl carbamates 8 (See for example U.S.Pat. No. 6,239,283, the entire contents of which are incorporatedherein; see also CHART VII and IX) can be converted to theoxazolidinone-5-carboxamide 9 using steps similar to those described inCHART I for the conversion of 1 to 5 using METHOD A. The sulfur group instructures 9 can then be oxidized with an appropriate oxidizing agentsuch as sodium periodate in an appropriate solvent such as mixtures ofmethanol and water or osmium tetroxide (cat.) and N-methylmorpholineN-oxide in an appropriate solvent such as mixtures of acetone and waterto give the corresponding sulfoxide and sulfone derivatives 10 (i=1, 2).The double bond in structures 10 may be reduced by catalytichydrogenation using an appropriate catalyst such as palladium-on-carbonin a suitable solvent such as methanol to give structures 11. See CHARTSVII, VII and IX for alternate preparations of the thiopyran-4-yl phenyloxazolidinone-5-carboxamides.

CHART III illustrates the preparation of the piperazinyl phenyloxazolidinone-5-carboxamides 15. The piperizinylphenyl carbamates 12(see for example J. Med. Chem. 1996, 39(3), 673-679) can be converted tothe oxazolidinone-5-carboxamide 13 using steps similar to thosedescribed in CHART I for the conversion of 1 to 5 using METHOD A. TheCBZ protecting group of 13 can be removed via hydrogenation in thepresence of an appropriate catalyst such as palladium-on-carbon orPearlman's catalyst in a solvent such as methanol, ethanol, ethylacetate or mixtures thereof, and the piperazine ring of 14 can then beacylated or alkylated by methods well known to those skilled in the artto give the targeted structures 15. In the case where R¹⁰⁷ isbenzyloxyacetyl, subsequent catalytic hydrogenation of 15 affords thehydroxyacetyl-substituted piperazinyl phenyl oxazolidinone-5-carboxamide15 (R¹⁰⁷═C(═O)CH₂OH). Alternatively, structures 12 can bebis-deprotected using methods known to one skilled in the art to givethe piperazinyl fluorobenzenamine intermediate which can then beconverted to structures 15 using steps similar to those described inCHART XII for the conversion 68 to 70.

CHART IV illustrates the preparation of the 3- and 4-pyridyl and4-pyranyl phenyl oxazolidinone-5-carboxamides 18, 20 and 21. Theiodophenyl carbamates 16 (see for example Org. Process Res. Dev. 2001,5(1), 80-83) can be converted to the 4-iodophenyloxazolidinone-5-carboxamide 17 using steps similar to those described inCHART I for the conversion of 1 to 5 using METHOD B. The aryl iodide 17can then be coupled with 3-(trimethylstannyl)pyridine (see EXAMPLE 7,step 4 below) or 4-(trimethylstannyl)pyridine (See U.S. Pat. No.5,990,136, the entire contents of which are incorporated herein) using apalladium catalyst system such astris(dibenzylideneacetone)dipalladium(0) and triphenylarsine in asolvent such as N-methyl-2-pyrrolidinone at an appropriate temperature,typically in a range of 50° C. to 100° C., to give structures 18. Thearyl iodide 17 can also be converted to the aryl stannane 19 upontreatment with hexamethylditin in the presence of a palladium catalystsuch as bis(triphenylphosphine)palladium(II) chloride in a solvent suchas 1,4-dioxane at an appropriate temperature, typically in a range from50° C. to 100° C. Coupling of this aryl stannane then with the vinyltriflate of tetrahydro-4H-pyran-4-one (See U.S. Pat. No. 5,968,962, theentire contents of which are incorporated herein.) at ambienttemperature using a catalyst system similar to that used to preparestructures 18 affords the pyranyl phenyl oxazolidinone-5-carboxamide 20.Subsequent catalytic hydrogenation affords structures 21.

CHART V illustrates the preparation of the thiomorpholinyl phenyl andfluorophenyl oxazolidinone-5-carboxamides 27. Nitrobenzenes 22 (Z₁₀=F,Cl, OTf or other leaving group) can be converted to structures 23 upontreatment with thiomorpholine in the presence of a base such asN,N-diisopropylethylamine in a suitable solvent such as acetonitrile ata temperature typically in a range from 25-80° C. Reduction of the nitrogroup of 23 using, for example, catalytic hydrogenation with anappropriate catalyst such as Raney Nickel in a suitable solvent systemsuch as a mixture of tetrahydrofuran and water gives the anilines 24which can be converted to structures 25 using steps similar to thosedescribed in CHART I for the conversion of 6 to 4 by METHOD C. Oxidationof the sulfur atom in structures 25 using the methods describedpreviously (see CHART II) affords the sulfoxide and sulfone derivatives26 which are converted to the targeted structures 27 as described inCHART I.

CHART VI illustrates an alternate preparation of the thiomorpholinyldifluorophenyl oxazolidinone-5-carboxamide 33. In this method, thephenyl thiomorpholine sulfone 29 is prepared by the treatment of2,6-difluoroaniline 28 with vinyl sulfone in the presence of aluminumchloride in a suitable solvent such as chlorobenzene at an elevatedtemperature. Nitration of the phenyl ring of 29 with fuming nitric acidin acetic acid at ambient temperature then affords the nitrobenzenestructure 30 which can then be converted to the aniline 31 as beforeunder catalytic hydrogenation conditions using a suitable catalyst suchas Raney Nickel. Treatment of the aniline 31 with an appropriate alkylor benzyl chloroformate in the presence of a base such as sodiumbicarbonate gives the carbamate structures 32 which can then beconverted to the targeted structures 33 using steps similar to thosedescribed in CHART I for the conversion of 1 to 5 using METHOD A.Alternatively, the aniline 31 can be converted to 33 using steps similarto those described in CHART I for the conversion of 6 to 5 using METHODC.

CHART VII illustrates an alternate preparation of the thiopyran-4-ylphenyl oxazolidinone-5-carboxamides 40. For structures 40 where R₂=H,4-bromo- or 4-iodoaniline 35 (Z₁₀=Br, I) can be converted to itsisobutyl carbamate derivative 36 (Z₁₀=Br, I) upon treatment withisobutyl chloroformate in the presence of an appropriate base such assodium bicarbonate in a suitable solvent system. Treatment of 36 withtwo equivalents of n-butyllithium in a suitable solvent such astetrahydrofuran at an appropriate temperature, typically in a range of−78 to −40° C., gives the dilithiated species resulting fromdeprotonation of the carbamate and metal-halogen exchange of the arylhalide. Subsequent treatment with tetrahydro-2H-thiopyran-4-one followedby warming to 0-25° C. affords the 4-hydroxythiopyran-4-yl phenylcarbamate 37 which can then be reduced to the thiopyran-4-yl phenylcarbamate 38 using, for example, excess triethylsilane intrifluoroacetic acid at ambient temperature. The isobutyl carbamategroup of 38 is readily cleaved upon treatment, for instance, withaqueous potassium hydroxide in ethylene glycol at an elevatedtemperature, 100° C. for example, to afford the aniline 39 which canthen be converted to the targeted structures 40 (R₂=H, i=1,2) usingsteps similar to those outlined in CHART V for the conversion of 24 to27. Alternatively, the sulfur atom of carbamate 38 can first be oxidizedusing the methods described previously (CHART II) to give thecorresponding sulfoxide and sulfone derivatives. The carbamate is thencleaved as described above to give aniline 39 S-oxide or S,S-dioxidewhich can then be converted to the structures 40 using steps similar tothose described in CHART I for the conversion of 6 to 5 using METHOD C.Note that the oxidations to give the sulfoxide products provide mixturesof cis and trans isomers which are separable by preparative HPLC.However selective oxidation methods exist for the formation of the transisomer (see Tetrahedron Lett. 2000, 4301-4305, and references citedtherein).

For structures 40 where one R₂=H and the other R₂=F, 3-fluoroaniline(Z₁₀=H) can be converted to the 4-hydroxythiopyran-4-yl phenyl carbamate37 via the carbamate 36 (Z₁₀=I, Br), as described in Org. Proc. Res.Dev. 2001, 5, 80-83 and Tetrahedron Lett. 2000, 4301-4305. Carbamate 37can then be converted to the targeted structures 40 (R₂, R₂=H, F; i=1,2) using the methods described above.

For structures 40 where R₂=F, 3,5-difluoroaniline (Z₁₀=H) can beconverted to its isobutyl carbamate derivative 36 as described above.Treatment of 36 with two equivalents of n-butyllithium in a suitablesolvent such as tetrahydrofuran at a suitable temperature, typically ina range of −78 to −40° C., gives the dilithiated species resulting fromdeprotonation of the carbamate and metallation at the para position(adjacent to the two fluorine atoms) of the phenyl ring. A chelatingadditive such as N,N,N′,N′-tetramethylethylenediamine (TMEDA) may beused in this reaction. Subsequent treatment withtetrahydro-2H-thiopyran-4-one followed by warming to 0-25° C. affordsthe 4-hydroxythiopyran-4-yl phenyl carbamate 37 which can then bereduced to the thiopyran-4-yl phenyl carbamate 38 upon treatment, forexample, with excess triethylsilane in trifluoroacetic acid at anelevated temperature, typically from 40 to 75° C. Carbamate 38 can thenbe converted to the targeted structures 40 (R₂=F, i=1, 2) using themethods described above.

CHART VIII illustrates an additional method for the preparation of thethiopyran-4-yl phenyl oxazolidinone-5-carboxamide sulfones 43. Thetetrahydrothiopyran ring of structures 41 (see CHART VII for thepreparation) can be oxidized using methods described previously (CHARTII) to give the corresponding sulfone structures 42. Carbamate 42 canthen be converted to the targeted structures 43 using steps similar tothose described in CHART I for the conversion of 1 to 5 through the5-hydroxymethyl oxazolidinone intermediate 2 using METHOD B.

CHART IX illustrates an additional method for the preparation of thethiopyran-4-yl difluorophenyl oxazolidinone-5-carboxamides 51.3,5-Difluoroaniline 44 can be protected as its 2,5-dimethylpyrrolederivative 45 upon treatment with acetonylacetone and catalytic amountsof p-toluenesulfonic acid in an appropriate solvent, such as mixtures oftoluene and tetrahydrofuran, at an appropriate temperature, typicallyfrom 40° C. to reflux. Treatment of 45 with n-butyllithium in a solventsuch as tetrahydrofuran at a suitable temperature, typically in a rangeof −78 to 40° C., gives the aryllithium species resulting fromdeprotonation at the para position (adjacent to the two fluorine atoms)of the phenyl ring. Subsequent treatment withtetrahydro-2H-thiopyran-4-one followed by warming to 0-25° C. affordsthe 4-hydroxythiopyran 46 which can be converted to the dihydrothiopyran47 using, for example, catalytic amounts of p-toluenesulfonic acid in anappropriate solvent such as benzene at an elevated temperature,typically from 60-120° C. The pyrrole protecting group can then beremoved upon treatment with excess hydroxylamine hydrochloride in thepresence of an appropriate base, such as triethylamine, in a suitablesolvent, such as mixtures of ethanol and tetrahydrofuran, at anappropriate temperature, typically 40-80° C., to give the aniline 48which is reprotected as the carbamate 49 using methods describedpreviously (CHART VI). The dihydrothiopyran ring of 49 can then bereduced upon treatment, for example, with excess triethylsilane intrifluoroacetic acid at an elevated temperature, typically from 40-80°C., to give the tetrahydrothiopyran 50 which can then be converted tothe targeted structures 51 (i=1,2) using the steps outlined in CHART VIIfor the conversion of 38 to 40.

CHART X illustrates the preparation of the N-alkylated benzothiazoloneand benzoxazolone oxazolidinone-5-carboxamides 58 (X₁=O, S; R₃₀₀=alkylor substituted alkyl). For the benzothiazolones (X=S),6-nitro-2-benzothiazolinones 52 (commercially available, known in theliterature or prepared using methods known to one skilled in the art)can be N-alkylated under conditions known to those skilled in the art(see J. Heterocyclic Chem., 1992, 29, 1069, and U.S. Pat. No. 6,069,160,the entire contents of which are incorporated herein, for specificexamples of interest), including treatment with an alkylating agent suchas iodomethane, dimethylsulfate, iodoethane, 2-iodopropane,bromoacetonitrile or 1-bromo-2-fluoroethane in the presence of a basesuch as sodium hydride, 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU), orpotassium carbonate in an suitable solvent such as dimethylformamide,tetrahydrofuran, acetonitrile or acetone at an appropriate temperature,typically from 0° C. to 100° C., to give structures 53 (X₁=S). For thebenzoxazolones (X₁=O), 6-nitro-2-benzoxazolones 55 (prepared, forexample, from 2-amino-5-nitrophenol 54 according to J. HeterocyclicChem., 1992, 29, 1069) can be N-alkylated to give 53 (X₁=O) underconditions described above for the benzothiazolinone 52 (see J.Heterocyclic Chem., 1992, 29, 1069; also see Pharmazie, 1971, 26, 280,and J. Am. Chem. Soc., 1958, 80, 1662, for alternate routes tostructures 53 (X₁=O)). Alternatively, 2-amino-5-nitrophenols 54 can bereductively alkylated with simple aldehydes or ketones, acetone forexample, in the presence of an appropriate reducing agent such as sodiumcyanoborohydride in a suitable solvent such as ethanol to givestructures 56 which can then be converted to structures 53 (X₁=O) upontreatment, for example, with 1,1′-carbonyldiimidazole under conditionssimilar to those used for the preparation of 55 from 54. Reduction ofthe nitro group of 53 using methods known to one skilled in the art, bycatalytic hydrogenation, for instance, over an appropriate catalyst suchas palladium-on-carbon or platinum oxide in a suitable solvent systemsuch as mixtures of tetrahydrofuran and methanol (see J. HeterocyclicChem., 1992, 29, 1069, for example), gives the aniline 57 which can thenbe converted to structures 58 (X₁=O, S) using steps similar to thosedescribed in CHART I for the conversion of 6 to 5 by METHOD C.

CHART XI illustrates the preparation of the indolinyloxazolidinone-5-carboxamides 67. Double deprotection of theaminoindoline 59 (for the (2R)-methyl derivative, see PCT/US00/08224;WO00/73301) using methods known to one skilled in the art, for examplecatalytic hydrogenation over an appropriate catalyst such aspalladium-on-carbon or Pearlman's catalyst in a suitable solvent,affords the aminoindoline 60. The 5-amino group is reprotected as its2,5-dimethyl-1H-pyrrole derivative 61 using the methods described inCHART IX for the conversion of 44 to 45, and the indoline nitrogen isreprotected as its benzyl carbamate using methods known to one skilledin the art to give structures 62. The pyrrole protecting group can thenbe removed using the methods described in CHART IX for the conversion of47 to 48 to give the aminoindoline 63 which is then converted tostructures 64 using the steps outlined in CHART I for the conversion of6 to 4 by METHOD C. The CBZ protecting group is then removed and theindoline nitrogen acylated or alkylated using methods known to oneskilled in the art to give 66 using steps similar to those described inCHART III for the conversion 13 to 15, and 66 is then converted to thetarget structures 67 as described in CHART I for the conversion of 4 to5. Alternatively, the aminoindoline 59 can be converted to the targetstructures 67 using steps similar to those described in CHART III forthe conversion of 12 to 15.

CHART XII illustrates the preparation of the azetidinyloxazolidinone-5-carboxamides 70. The azetidines 68 (prepared using stepssimilar to those described in PCT/US96/12766) can be acylatedselectively on the ring nitrogen using methods known to those skilled inthe art to give structures 69 which can then be converted to thetargeted structures 70 using steps similar to those described in CHART Ifor the conversion of 6 to 5.

CHART XIII illustrates a general synthesis of the thiadiazinoneoxazolidinone-5-carboxamides 77. First, a nitrobenzene carboxylic acid71 is coupled with a suitable N-protected hydrazine reagent, such asN-(tert-butoxycarbonyl)hydrazine. This reaction can be performed withany number of known coupling reagents, such as HATU or carbodiimides.The coupling reaction is typically performed in a polar aprotic solvent,such as dimethylformamide, acetonitrile, or mixtures thereof, inpresence of an organic base, such as triethylamine or(N,N-diisopropyl)ethylamine (DIEA). The process is typically carried outbetween about 0° C. to about 50° C. Next, the hydrazide is convertedinto the thiohydrazide 73 with a Lawesson's reagent under conditionswell precedented in the chemical literature. This conversion may beconducted in suitable organic solvent, such as dioxane ortetrahydrofuran, and is typically performed at temperatures in a rangeof from about 25° C. to about 100° C. By way of example, Lawesson'schemistry is reviewed by Cava et al. in Tetrahedron, 1985, vol. 41, pp.5061-5087. The next step involves an alkylation of the resultingprotected thiohydrazide reagent with a suitable alpha-substituted esterreagent (such as methyl or ethyl ester) to give structures 74. The esterbears a good leaving group in a position alpha to the esterfunctionality, e.g., bromo, iodo, nitrobenzenesulfonyloxy, mesyloxy(OMs), or a like group. The reaction is typically performed in a polarorganic solvent such as acetonitrile, tetrahydrofuran, ordimethylformamide in the presence of an organic or inorganic base, suchas potassium carbonate, pyridine, or triethylamine. A typical range oftemperatures for this transformation is from about 0° C. to about 50° C.The following step involves deprotection of an acid-sensitivethiohydrazide protective group (exemplified by Boc in this case). Underreaction conditions, the acid-induced N-deprotection is immediatelyfollowed by a high-yielding heterocyclization into the desiredthiadiazinone derivative 75. This transformation is convenientlyperformed in the presence of organic or inorganic acids, such astrifluoroacetic acid or hydrogen chloride. The reaction is carried outin organic solvent, such as dichloromethane, dichloroethane, dioxane, ortetrahydrofuran, at temperatures in a range from about 10° C. to about60° C. The nitro group is then reduced using methods known to oneskilled in the art to give the aniline 76. This reduction can beaccomplished by reacting the nitro intermediate with iron metal. Thereaction is carried out at temperatures between 60° C. and 90° C. inmixtures of water and alcohol (methanol, ethanol, etc.) as solvent, andin the presence of ammonium chloride to buffer the reaction mixture. Theaniline is then converted to the targeted structures 77 using stepssimilar to those described in CHART I for the conversion of 6 to 5.

Syntheses of dihydropyridones are well precedented in the prior art.Thus, dihydropyridone compounds can be made by variations of oxidativetransformations of piperidone derivatives exemplified by the followingreferences: Stutz et al. in Tetrahedron Lett., 1973, pp. 5095-5098; Doddet al., Tetrahedron Lett., 1991, pp. 3643-3646; Evans et al.,Tetrahedron Lett., 1995, pp. 3985-3988; Blache et al., Heterocycles,1997, pp. 57-69; and Ishii et al., Tetrahedron Lett., 1997, pp.7565-7568. In another embodiment, dihydropyridone compounds can besynthesized by variations of hetero Diels-Alder transformations of iminederivatives exemplified by the following publications: Diez et al.,Heterocycles, 1990, p. 485; Waldmann et al., Tetrahedron, 1993, pp.397-416; Lock et al., Tetrahedron lett., 1996, pp. 2753-2756; Kirschbaumet al., Tetrahedron Lett., 1997, pp. 2829-2832; Kirschbaum et al., Chem.Eur. J., 1997, pp. 143-151; and Kirschbaum et al., J. Org. Chem, 1998,pp. 4936-4946. In yet another embodiment, dihydropyridone compounds canbe prepared by reductive transformations of pyridine and pyridonederivatives, see, e.g. references: Haider, et. al., Helv. Chim. Acta,1975, p. 1287; Guerry et al., Synthesis, 1984, p. 485; Guerry et al.,Chimia, 1987, p. 341; Comins et al., Heterocycles, 1994, pp. 1121-1140;and Dehmlow et al., Heterocycles, 1994, pp. 355-366.

CHART XIV illustrates one general method for the preparation of thedihydropyridone oxazolidinone-5-carboxamides from nitrobenzene andpiperidine derivatives. Step 1 involves a nucleophilic aromaticsubstitution reaction of a suitable nitrobenzene 78 (Z₁₀=F, Cl, OTf orother leaving group) with a piperidine derivative, such as 4-piperidone,to give structures 79. This reaction is performed in aprotic polarsolvent such as dimethylformamide, acetonitrile, or dimethylsulfoxide inthe presence of an organic or inorganic base, such as pyridine,triethylamine, or potassium carbonate. Temperatures in the range ofabout 20° C. to about 80° C. are generally suitable for this reaction.The next step involves formation of a silyl enolate 80 from the1-arylpiperidone intermediate 79 and a silylating agent, such astriisopropylsilyl chloride, trialkylsilyl triflate, or a similarreagent. This reaction is typically conducted in the presence of anorganic base, such as triethylamine, pyridine, or imidazole attemperatures from about 0° C. to about 60° C. Step 3 of this synthesisinvolves an oxidation of the silyl enolate intermediates to thedihydropyridone compounds 81 with a suitable inorganic oxidant, such asceric ammonium nitrate (CAN; described by Evans et al. in TetrahedronLett., 1995, vol. 36, pp. 3985-3988) or palladium acetate (as describedby Comins et al. in Tetrahedron Lett., 1995, vol. 36, pp. 9449-9452).The nitro group of 81 can then be reduced using methods known to oneskilled in the art, for example through an iron metal reduction (seeCHART XIII) or through catalytic hydrogenation over palladium/CaCO₃ inthe presence of acetic acid, to give the aniline 82 which is thenconverted to the targeted structures 83 (W₁₀=O) using steps similar tothose described in CHART I for the conversion of 6 to 5. Oximederivatives of 83 can then be prepared using methods known to oneskilled in the art. The simple oxime (W₁₀=N(OH)) can be prepared from 83upon treatment hydroxylamine hydrochloride in the presence of anappropriate base such as pyridine which can also be used as the solventor as part of a solvent mixture.

CHART XV illustrates the preparation of the benzoxazin-3-one,benzothiazin-3-one and tetrahydroquinolin-2-oneoxazolidinone-5-carboxamides 88. Structures 84 (Z₅=O, S, CH₂, etc.),which are known in the literature (see WO99/37641 and WO99/40094 andreferences cited therein for specific examples) or can be prepared usingknown methods (such as nitration of the parent bicyclic ring system),can be alkylated using methods described previously (see CHART X) togive 85. The nitro group is then reduced using methods known to oneskilled in the art, for example through an iron metal reduction (seeCHART XIII) or through catalytic hydrogenation, to give the aniline 86which can then be converted to the target structures 88 (V₁=O) usingsteps similar to those described in CHART I for the conversion of 6 to5. In addition, the thioxo derivatives (V₁=S) can be prepared fromintermediate structures 87 (V₁=O). Treatment of 87 (V₁=O) withLawesson's reagent under conditions well precedented in the literature(see CHART XIII) affords the thioxo intermediates 87 (V₁=S) which canthen be converted to the target structures 88 (V₁=S) as describedpreviously.

CHART XVI illustrates general methods for the preparation of thethiopyran sulfoximine oxazolidinone-5-carboxamides 95. Sulfoxidestructures 89 in either the cis or trans configuration (prepared asoutlined in CHART VII or using methods similar to those described inU.S. Pat. No. 6,239,283) can be converted to the sulfoxinmines 90 withretention of the sulfoxide stereochemistry using amination methods knownto one skilled in the art, for example through treatment withO-mesitylene sulfonylhydroxylamine (MSH) in a suitable solvent such asmethylene chloride generally at or near ambient temperature (see alsoWO01/46185 and Synthesis, 2000, 1, 1). Sulfoximines 90 can then beconverted to the targeted structures 95 (R₃₁₅=H) using steps similar tothose described in CHART VII for the conversion of 38 to 39 followed bythose in CHART I for the conversion of 6 to 5. The sulfoximines 90 canalso be alkylated to give structures 91 (where R₃₁₅ is alkyl orsubstituted alkyl), for example through reaction with an aldehyde orketone, triethylsilane and trifluoroacetic acid in a suitable solventsuch as acetonitrile at a temperature, depending on the solvent, in therange of 10-120° C. or through reaction with an aldehyde or ketone andformic acid using Leuckart-Wallach or Eschweiler-Clarke conditions.Para-formaldehyde is a convenient source of formaldehyde for thisreaction to afford the N-methyl derivatives (see WO01/46185 foradditional methods for the functionalization of the sulfoximine group).The substituted sulfoximines 91 can then be converted to the targetstructures 95 as described previously. Alternatively, the alkylation canbe carried out as the last step in the sequence using structures 95(R₃₁₅=H).

The amination can also be carried out at a later stage in the synthesisstarting from the sulfoxide structures 92. These structures can beprepared from the carbamates 89 as described previously or using themethods outlined in CHART VII. Amination of 92 under the conditionsdescribed previously affords the sulfoximines 93 which can then beconverted to the target structures 95 (R₃₁₅=H) as before. Thesulfoximine group can also be functionalized as described above.

The corresponding thiomorpholine sulfoximine derivatives where thethiopyran ring in 95 is replaced with a thiomorpholine ring can beprepared using steps similar to those described above. However, theamination is generally carried out using sodium azide in polyphosphoricacid at a temperature generally in a range from about 40° C. to about70° C.

CHART XVII illustrates one method for the preparation of thedihydrothiazinyl sulfone oxazolidinone-5-carboxamides 98. Thethiomorpholine S,S-dioxide oxazolidinone-5-carboxamides 96 (see CHART V)can be converted to the dihydrothiazine derivatives 97 upon treatmentwith a suitable organic oxidant such as2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or chloranil. Thistransformation is typically performed in a polar organic solvent, suchas dioxane, tetrahydrofuran or dimethylacetamide, at a temperature inthe range of about 60° C. to about 110° C. Structures 97 can then beconverted to the targeted structures as described previously in CHART I.

CHART XVIII illustrates one method for the preparation of thetetrahydropyridyl or piperidinyl oxazolidinone-5-carboxamides 102. Thetetrahydropyridyl aniline derivatives 99 (See WO 97/09328 or WO99/64417) can be converted to the tetrahydropyridyl oxazolidinonederivatives 100 via Method C described above with respect to Chart I.Removing the protecting group (Z₁₂=Cbz, BOC, or Bn) using known methodsaffords the deprotected derivatives 101. Conservation of the double bondin the tetrahydropyridyl group may be accomplished by removing the Cbzwith a treatment of TMSI followed by methanol, BOC with a treatment ofTFA, or Bn with a treatment of x-chloroethyl chloroformate followed byMeOH. For Z₁₂=Bn or Cbz, cleavage of the protecting group undercatalytic hydrogenation conditions results in reduction of the doublebond to give the piperidinyl structure 101. Functionalization of thetetrahydropyridyl or piperidinyl nitrogen may be performed by knownmethods, such as by alkylation and acylation. (See also WO 99/64417,WO02/096916, and WO01/40236)

Suitable intermediates useful in preparating compounds of this inventionand additional synthetic methods to assist in producing the compoundsmay be found, for example, in the following publications, each of whichis hereby incorporated by reference.

U.S. Pat. Nos. 5,225,565; 5,182,403; 5,164,510; 5,247,090; 5,231,188;5,565,571; 5,547,950; 5,529,998; 5,627,181; 5,843,967; 5,861,413;5,827,857; 5,869,659; 5,952,324; 5,968,962; 5,688,792; 6,069,160;6,239,152; 5,792,765; 4,705,799; 5,043,443; 5,652,238; 5,827,857;5,529,998; 5,684,023; 5,627,181; 5,698,574; 6,166,056; 6,194,441;6,110,936; 6,069,145; 6,271,383; 5,981,528; 6,051,716; 6,043,266;6,313,307; 5,614,535; 6,239,283; 5,990,136; and 5,523,403.

PCT Application and publications PCT/US93/04850, WO94/01110;PCT/US94/08904, WO95/07271; PCT/US95/02972, WO95/25106; PCT/US95/10992,WO96/13502; PCT/US96/05202, WO96/35691; PCT/US96/12766; PCT/US96/13726;PCT/US96/14135; PCT/US96/17120; PCT/US96/19149; PCT/US97/01970;PCT/US95/12751, WO96/15130, PCT/US96/00718, WO96/23788, WO98/54161,WO99/29688, WO99/03846, WO99/37641, WO99/37652, WO99/40094, WO97/30995,WO97/09328, WO01/81350, WO01/40236, WO00/21960 WO01/04022, WO00/73301,WO01/46185, WO99/64417, WO02/59155, WO02/096916 and WO95/07271.

In some embodiments, the antibacterial compounds are prodrugs of thecompounds of formulae I, II, and III. The expression “prodrug” denotes aderivative of a known direct acting drug, which is transformed into theactive drug by an enzymatic or chemical process. Prodrugs of thecompounds of formulea I, II, and III are prepared by modifyingfunctional groups present on the compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound. Prodrugs include, but are not limited to, compoundsof structure I, II, and III wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to the animal, cleavesto form the free hydroxyl, amino or sulfhydryl group, respectively.Representative examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups. See Notari, R. E., “Theory and Practice of ProdrugKinetics,” Methods in Enzymology, 112:309-323 (1985); Bodor, N., “NovelApproaches in Prodrug Design,” Drugs of the Future, 6(3):165-182 (1981);and Bundgaard, H., “Design of Prodrugs: Bioreversible-Derivatives forVarious Functional Groups and Chemical Entities,” in Design of Prodrugs(H. Bundgaard, ed.), Elsevier, N.Y. (1985).

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Example 1(5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide—MethodA

Step 1: Preparation of(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid

A solution of benzyl 3-fluoro-4-(4-morpholinyl)phenylcarbamate (J. Med.Chem. 1996, 39(3), 673-679, 2.50 g, 7.57 mmol) in dry tetrahydrofuran(37.8 mL) at −78° C. under nitrogen is treated with n-butyllithium (1.6Min hexanes, 4.82 mL, 7.72 mmol) dropwise and stirred at −78° C. for 30minutes. The cooling bath is removed and the mixture is allowed toslowly warm to −40° C., at which point potassium (2R)-glycidate (J. Org.Chem. 1992, 57(12), 3380-3387, 974 mg, 7.72 mmol) is added. Aftersubsequent warming to ambient temperature, the resulting mixture isvigorously stirred for 2.75 days and then quenched with saturatedaqueous ammonium chloride (20 mL), diluted with water (20 mL) andextracted with ethyl acetate (2×75 mL) to remove the remaining starting.The aqueous phase is adjusted to pH 2 with 1M aqueous hydrochloric acid,saturated with sodium chloride and extracted with methylene chloride(5×100 mL), and this combined organic phase is dried over anhydroussodium sulfate and concentrated under reduced pressure to give the crudeproduct. The product mixture is then chromatographed on a Flash 40Msilica gel (90 g, 32-63 μm) cartridge, eluting with a gradient ofacetonitrile/methylene chloride (10/90-40/60) containing 1% formic acid,and those fractions with an R_(f)=0.15 by TLC (acetonitrile/methylenechloride, 50/50+1% formic acid) are pooled and concentrated to give thetitle compound, ¹H NMR (400 MHz, DMSO-d₆) δ 13.7 (bs, 1H), 7.48 (dd,1H), 7.23 (m, 1H), 7.05 (t, 1H), 5.17 (dd, 1H), 4.30 (t, 1H), 4.06 (dd,1H), 3.73 (m, 4H), 2.96 (m, 4H); MS (ESI+) for C₁₄H₁₅FN₂O₅ m/z 311(M+H)⁺; [α]²⁵ _(D)=−38° (c 0.94, DMSO).

Step 2: Preparation of(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

To a flame-dried flask containing(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid (Step 1, 250 mg, 0.806 mmol) under nitrogen is added oxalylchloride (4 mL) with stirring. The flask is capped with a drying tube,and the mixture is stirred at ambient temperature for 15 h and thenconcentrated under reduced pressure to give the acid chlorideintermediate [MS (ESI+) m/z 325 (M+H)⁺ observed for the methyl esterobtained by reaction of the acid chloride with methanol] which is usedwithout further purification. This intermediate is then taken up inanhydrous tetrahydrofuran (8 mL) under nitrogen, cooled to 0° C., andammonia (g) is bubbled in for 5 minutes. The resulting mixture is cappedwith a drying tube, stirred at ambient temperature for 1 h, and thendiluted with water (20 mL) and extracted with methanol/chloroform(10/90, 2×30 mL). The combined organic phase is dried over anhydroussodium sulfate and concentrated under reduced pressure, and the productmixture is recrystallized from ethyl acetate/hexane to give the titlecompound, mp 185-187° C. (decomp.); MS (ESI+) for C₁₄H₁₆FN₃O₄ m/z 310(M+H)⁺; [α]²⁵ _(D)=−23° (c 0.89, DMSO).

Example 2(5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-methyl-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 1, Step 2, and makingnon-critical variations but substituting methylamine for ammonia, thetitle compound is obtained, mp 182-183° C. (decomp.); MS (ESI+) forC₁₅H₁₈FN₃O₄ m/z 324 (M+H)⁺; [α]²⁵ _(D)=−39° (c 0.92, DMSO).

Example 3 (5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-allyl-2-oxo-5-oxazolidinecarboxamide

To a flame-dried flask under nitrogen is added allylamine (0.60 mL, 8.05mmol). The flask is cooled in an ice bath, and a solution of(5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarbonylchloride (EXAMPLE 1, Step 2, 0.805 mmol theory) in anhydroustetrahydrofuran (8.0 mL) is added. The resulting mixture is stirredunder nitrogen for 2 h, allowing the cooling bath to slowly expire, andis then diluted with water (10 mL) and extracted with methylene chloride(20 mL). The organic phase is washed with water (10 mL) and saline (10mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure, and the crude product is chromatographed on a Flash 40S silicagel (40 g, 32-63 μm) cartridge, eluting with a gradient ofmethanol/methylene chloride (0.5/99.5-2/98). Pooling and concentrationof those fractions with an R_(f)=0.44 by TLC (methanol/chloroform, 5/95)provides the title compound, mp 167-169° C.; MS (ESI+) for C₁₇H₂₀FN₃O₄m/z 350 (M+H)⁺; [α]²⁵ _(D)=−44° (c 0.94, DMSO).

Example 4(5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-propyl-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 3, and making non-criticalvariations but substituting propylamine for allylamine and trituratingand filtering the final product from methanoldiethyl ether, the titlecompound is obtained, mp 165-167° C.; MS (ESI+) for C₁₇H₂₂FN₃O₄ m/z 352(M+H)⁺; [α]²⁵ _(D)=−43° (c 1.02, DMSO).

Example 5(5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-methoxy-2-oxo-5-oxazolidinecarboxamide

A mixture of(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid (EXAMPLE 1, Step 1, 150 mg, 0.483 mmol) and O-methylhydroxylaminehydrochloride (61 mg, 0.724 mmol) in tetrahydrofuran/water (1/1, 4.8 mL)is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (278 mg, 1.45 mmol), and the resulting mixture is stirredat ambient temperature for 30 minutes and is then diluted with water (10mL) and extracted with ethyl acetate (2×20 mL). The combined organicphase is washed with water (10 mL) and saline (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure, andthe crude product is chromatographed on a Flash 40S silica gel (40 g,32-63 μm) cartridge, eluting with methanoumethylene chloride (2.5/97.5).Pooling and concentration of those fractions with an R_(f)=0.53 by TLC(methanol/chloroform, 10/90) gives the title compound, mp 206-208° C.(decomp.); MS (ESI+) for C₁₅H₁₈FN₃O₅ m/z 340 (M+H)⁺; [α]²⁵ _(D)=−56° (c0.92, DMSO).

Example 6(5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-hydroxy-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-N-benzyloxy-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 5, and making non-criticalvariations but substituting O-benzylhydroxylamine hydrochloride forO-methylhydroxylamine hydrochloride, the title compound is obtained, mp191-193° C. (decomp.); MS (ESI+) for C₂₁H₂₂FN₃O₅ m/z 416 (M+H)⁺; [α]²⁵_(D)=−46 (c 0.93, DMSO).

Step 2: Preparation of(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-N-hydroxy-2-oxo-5-oxazolidinecarboxamide

To a mixture of(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-N-benzyloxy-2-oxo-5-oxazolidinecarboxamide (Step 1, 300 mg, 0.722 mmol) in methanol(28.8 mL) is added 5% palladium-on-carbon (77 mg) under nitrogen. Theresulting mixture is degassed and stirred under a hydrogen atmosphere(balloon) for 1 h. The catalyst is then removed by filtration throughCelite, rinsing with methanol (60 mL), and the filtrate is concentratedunder reduced pressure. Trituration of this residue with (5% methanolmethylene chloride)/diethyl ether gives the title compound, mp 141-143°C.; MS (ESI+) for C₁₄H₁₆FN₃O₅ m/z 326 (M+H)⁺; [α]²⁵ _(D)=−70° (c 0.99,DMSO).

Example 7(5R)-(−)-3-[4-(3-Pyridyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of(5R)-(−)-3-[3-fluoro-4-iodophenyl]-5-hydroxymethyl-2-oxazolidinone

A solution of isobutyl 3-fluoro-4-iodophenylcarbamate (Org. Process Res.Dev. 2001, 5(1), 80-83, 5.00 g, 14.83 mmol) in dry tetrahydrofuran (59mL) at −78° C. under nitrogen is treated with lithiumhexamethyldisilazide (1.0M in tetrahydrofuran, 15.6 mL, 15.57 mmol)dropwise and stirred at −78° C. for 45 minutes. Then, (R)-glycidylbutyrate (2.21 mL, 15.57 mmol) is added dropwise, and the resultingmixture is stirred at −78° C. for 1 h and at ambient temperature for2.75 days. The reaction mixture is then quenched with saturated aqueousammonium chloride (20 mL), diluted with water (20 mL) and the layers areseparated. The aqueous phase is extracted with ethyl acetate (25 mL),and the combined organic phase is washed with water (25 mL) and saline(25 mL), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The product mixture is then chromatographed on a Flash40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient ofmethanol/methylene chloride (1/99-2/98), and those fractions with anR_(f)=0.25 by TLC (methanol/chloroform, 5/95) are pooled andconcentrated to give the title compound, mp 116-117° C.; MS (ESI+) forC₁₀H₉FINO₃ m/z 338 (M+H)⁺; [α]²⁵ _(D)=−41 (c 0.98, DMSO).

Step 2: Preparation of(−)-methyl(5R)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxylate

A solution of(5R)-(−)-3-[3-fluoro-4-iodophenyl]-5-hydroxymethyl-2-oxazolidinone (Step1, 7.61 g, 22.58 mmol) in acetone (150 mL) at −10° C. is treated with amixture of CrO₃ (6.21 g, 62.1 mmol) in sulfuric acid (6M, 16.9 mL, 101mmol) dropwise over 15 minutes. The resulting mixture is allowed toslowly warm to ambient temperature with vigorous stirring (slightexotherm to 35° C.) and is stirred for an additional 16 h. The mixtureis then treated with isopropanol (35 mL), diluted with saline (150 mL)and diethyl ether (150 mL), stirred until all solids are dissolved, andthe layers are separated. The aqueous phase is extracted with diethylether (100 mL), and the combined organic phase is dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give thecrude carboxylic acid intermediate which is taken up in methanol (225mL) and treated with concentrated sulfuric acid (8 drops). The resultinghomogeneous mixture is stirred at ambient temperature for 20 h and isthen concentrated under reduced pressure to give the crude methyl esterproduct which is chromatographed on two Flash 40M 90 g silica gel (32-63μm) cartridges, eluting with a gradient of ethyl acetate/heptane(20/80-40/60). Pooling and concentration of those fractions with anR_(f)=0.36 by TLC (ethyl acetate/hexane, 50/50) gives the titlecompound, mp 106-109° C.; MS (ESI+) for C₁₁H₉FINO₄ m/z 366 (M+H)⁺; [α]²⁵_(D)=−30 (c 0.93, DMSO).

Step 3: Preparation of(5R)-(−)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxamide

A solution of(−)-methyl(5R)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxylate(Step 2, 6.23 g, 17.1 mmol) in acetonitrile (85 mL) is treated withconcentrated ammonium hydroxide (85 mL), and the resulting mixture isstirred at ambient temperature for 1 h. The mixture is then diluted withsaline (100 mL) and extracted with methylene chloride (3×100 mL), andthe combined organic phase is washed with saline (100 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product is diluted with hot ethyl acetate (200 mL) and filtered toremove inorganic residue, and the filtrate is diluted with hexanes (300mL). The resulting precipitate is isolated by filtration to give thetitle compound, mp 176-178° C.; MS (ESI+) for C₁₀H₈FIN₂O₃ m/z 351(M+H)⁺; [α]²⁵ _(D)=−19 (c 0.97, DMSO).

Step 4: Preparation of 3-(trimethylstannyl)pyridine

A mixture of hexamethylditin (654 mg, 1.99 mmol), 3-bromopyridine (300mg, 1.90 mmol) and bis(triphenylphosphine)palladium(II) chloride (40 mg,0.057 mmol) in 1,4-dioxane (9.5 ml) is degassed, heated up to 90° C.under nitrogen, stirred at this temperature for 2.5 h and at ambienttemperature overnight, and is then concentrated under reduced pressure.The product mixture is chromatographed on a Flash 40S 40 g silica gel(32-63 μm) cartridge, eluting with ethyl acetate/heptane (20/80), andthose fractions with an R_(f)=0.47 by TLC (ethyl acetate/hexane, 50/50)are pooled and concentrated to give the title compound (see Chem. Pharm.Bull. 1982, 30(5), 1731-1737 for characterization).

Step 5: Preparation of(5R)-(−)-3-[4-(3-pyridyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

A mixture of(5R)-(−)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxamide (Step3, 422 mg, 1.21 mmol), 3-(trimethylstannyl)pyridine (Step 4, 350 mg,1.45 mmol), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.0242mmol), triphenylarsine (59 mg, 0.194 mmol) and copper(I) iodide (9 mg,0.0484 mmol) in N-methyl-2-pyrrolidinone (4.8 mL) under nitrogen isdegassed, heated up to 50° C. and stirred at this temperature for 2days, during which additional tris(dibenzylideneacetone)dipalladium(0)(22 mg, 0.0242 mmol), triphenylarsine (59 mg, 0.194 mmol) and copper(I)iodide (9 mg, 0.0484 mmol) are added. The resulting mixture is dilutedwith water (15 mL) and extracted with methylene chloride (3×20 mL), andthe combined organic phase is dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting oil is diluted withethyl acetate (25 mL) and extracted with aqueous hydrochloric acid (1M,25 mL), and the aqueous phase is neutralized with sodium hydroxide (s),saturated with sodium chloride and extracted with methylene chloride(3×25 mL) containing a small amount of methanol. This combined organicphase is dried over anhydrous sodium sulfate and concentrated underreduced pressure, and the residue is recrystallized from ethylacetate/hexane to give the title compound, mp 240-242° C. (dec.); MS(ESI+) for C₁₅H₁₂FN₃O₃ m/z 302 (M+H)⁺; [α]²⁵ _(D)=−25 (c 0.94, DMSO).

Example 8(5R)-(−)-3-[4-(4-Pyridyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 7, Step 5, and makingnon-critical variations but substituting 4-(trimethylstannyl)pyridine(U.S. Pat. No. 5,990,136; 23 Nov. 1999) for3-(trimethylstannyl)pyridine, the title compound is obtained, mp256-259° C. (dec.); MS (ESI+) for C₁₅H₁₂FN₃O₃ m/z 302 (M+H)⁺; [α]²⁵_(D)=−27 (c 0.94, DMSO).

Example 9(5R)-(−)-3-[4-(3,6-Dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of(5R)-3-[4-(trimethylstannyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

A mixture of(5R)-(−)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxamide(EXAMPLE 7, Step 3, 3.50 g, 10.0 mmol), hexamethylditin (3.44 g, 10.5mmol) and bis(triphenylphosphine)palladium(II) chloride (140 mg, 0.200mmol) in 1,4-dioxane (50 mL) under nitrogen is degassed, heated up to90° C. and stirred at 90° C. for 2 h and at ambient temperatureovernight. The resulting mixture is concentrated under reduced pressureto remove dioxane, diluted with methylene chloride (75 mL), washed withsaline (25 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue is chromatographed on a Flash 40M 90g silica gel (32-63 μm) cartridge, eluting with a gradient ofmethanol/methylene chloride (1/99-2/98), and those fractions with anR_(f)=0.26 by TLC (methanol/chloroform, 5/95) are pooled andconcentrated to give the title compound, ¹H NMR (400 MHz, CDCl₃) δ 7.38(m, 2 H), 7.20 (m, 1 H), 6.65 (s, 1 H), 5.82 (s, 1 H), 5.00 (dd, 1 H),4.26 (m, 2 H), 0.35 (m, 9 H).

Step 2: Preparation of(5R)-(−)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

A mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonic acidester (U.S. Pat. No. 5,968,962, 19 Oct. 1999, 682 mg, 2.94 mmol),tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.0588 mmol) andtriphenylarsine (144 mg, 0.470 mmol) in N-methyl-2-pyrrolidinone (14.7mL) is degassed and stirred under nitrogen for 5 minutes.(5R)-3-[4-(Trimethylstannyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide(Step 1, 1.14 g, 2.94 mmol) is then added, and the resulting mixture isstirred at ambient temperature for 5 days. The reaction mixture is thendiluted with water (25 mL) and extracted with ethyl acetate (3×30 mL),and the combined organic phase is washed with water (3×30 mL) and saline(20 mL), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The crude product mixture is chromatographed on aFlash 40M 90 g silica gel (32-63 μm) cartridge, eluting with a gradientof methanol/methylene chloride (1/99-2.5/97.5), and those fractions withan R_(f)=0.40 by TLC (methanol/chloroform, 2×5/95) are pooled andconcentrated to give the title compound, mp 164-169° C.; MS (ESI−) forC₁₅H₁₅N₂O₄F m/z 305 (M−H)⁻; [α]²⁵ _(D)=−23 (c 0.96, DMSO).

Example 10(5R)-(−)-3-[4-(Tetrahydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

A mixture of(5R)-(−)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide(EXAMPLE 9, Step 2, 200 mg, 0.653 mmol) and 10% palladium-on-carbon (139mg, 0.131 mmol) in methanol (26 mL) is shaken under a 40 psi hydrogenatmosphere on a Parr apparatus for 5 h. The catalyst is then removed byfiltration through a pad of Celite, and the filtrate is concentratedunder reduced pressure and chromatographed on a Flash 40S 40 g silicagel (32-63 μm) cartridge, eluting with a gradient of methanol/methylenechloride (2/98-3/97). Pooling and concentration of those fractions withan R_(f)=0.37 by TLC (methanol/chloroform, 2×5/95) gives the titlecompound, mp 153-156° C.; MS (ESI−) for C₁₅H₁₇N₂O₄F m/z 307 (M−H); [α]²⁵_(D)=−21 (c 0.87, DMSO).

Example 11(5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

Step 1: Preparation of(−)-methyl(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 1, Step 1, and makingnon-critical variations but substituting isobutyl4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenylcarbamate (WO 00/44741,3 Aug. 2000) for benzyl 3-fluoro-4-(4-morpholinyl)phenylcarbamate, thecrude (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylic acid intermediate isobtained and is used without further purification. This intermediate(540 mg crude) is taken up in methanol (16 mL), a drop of concentratedsulfuric acid is added, and the mixture is stirred at ambienttemperature for 21 h. Then, the reaction mixture is concentrated underreduced pressure and chromatographed on a Flash 40S 40 g silica gel(32-63 μm) cartridge, eluting with ethyl acetate/heptane (25/75).Pooling and concentration of those fractions with an R_(f)=0.25 by TLC(ethyl acetate/hexs, 50/50) give the title compound, mp 106-110° C.; MS(ESI+) for C₁₆H₁₆NO₄FS m/z 338 (M+H)⁺; [α]²⁵ _(D)=−36 (c 0.99, DMSO).

Step 2: Preparation of(5R)-(−)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 7, Step 3, and makingnon-critical variations but substituting(−)-methyl(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) for(−)-methyl(5R)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxylateand purifying the product by recrystallization from methanol/diethylether, the title compound is obtained, mp 182-184° C. (dec.); MS (ESI−)for C₁₅H₁₅FN₂O₃S m/z 321 (M−H)⁻; [α]²⁵ _(D)=−24 (c 0.93, DMSO).

Step 3: Preparation of(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

A mixture of(5R)-(−)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide(Step 2, 294 mg, 0.912 mmol) in methanol (18 mL) is treated with sodiumperiodate (205 mg, 0.958 mmol) in water (3.8 mL), and the mixture isstirred at ambient temperature for 44 h. The resulting mixture isdiluted with water (25 mL) and extracted with methylene chloride (5×30mL), and the combined organic phase is dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude productmixture is triturated with acetone/diethyl ether and then filtered togive the title compound as a mixture of two diastereomers, ¹H NMR (400MHz, DMSO-d₆) δ 7.87 (s, 1 H), 7.63 (s, 1 H), 7.52 (d, 1 H), 7.39 (m, 2H), 5.83 (m, 1 H), 5.04 (dd, 1 H), 4.29 (t, 1 H), 4.02 (dd, 1 H), 3.65(m, 1 H), 3.39 (m, 1 H), 3.10 (m, 1 H), 2.92 (m, 2 H), 2.54 (m, 1 H); MS(ESI+) for C₁₅H₁₅FN₂O₄S m/z 339 (M+H)⁺.

Example 12(5R)-(−)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

A solution of(5R)-(−)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide(EXAMPLE 11, Step 2, 209 mg, 0.648 mmol) in water/acetone (25/75, 13 mL)under nitrogen is treated with N-methylmorpholine N-oxide (190 mg, 1.62mmol) and osmium tetroxide (2.5 wt % in tBuOH, 0.41 mL, 0.0324 mmol),and the mixture is stirred at ambient temperature for 43 h. The reactionis then treated with ½-saturated aqueous sodium bisulfite (25 mL) andextracted with methylene chloride (3×25 mL), and the combined organicphase is dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue is chromatographed on a Flash 40S 40 gsilica gel (32-63 μm) cartridge, eluting with a gradient ofmethanol/methylene chloride (2.5/97.5-4196), and those fractions with anR_(f)=0.48 by TLC (methanol/chloroform, 10/90) are pooled andconcentrated to give the title compound, mp 206-208° C.; MS (ESI−) forC₁₅H₁₅FN₂O₅S m/z 353 (M−H)⁻; [α]²⁵ _(D)=−20 (c 0.98, DMSO).

Example 13(5R)-(−)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

A mixture of(5R)-(−)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide (EXAMPLE 12, 73 mg, 0.206 mmol) and 10% palladium-on-carbon(44 mg, 0.0412 mmol) in methanol (21 mL) is shaken under a 40 psihydrogen atmosphere on a Parr apparatus for 16 h. The catalyst is thenremoved by filtration through a pad of Celite, rinsing with methanol andtetrahydrofuran, and the filtrate is concentrated under reduced pressureand triturated with (5% methanol/methylene chloride)/diethyl ether.Filtration then provides the title compound, mp 229-231° C. (dec.); MS(ESI−) for C₁₅H₁₇FN₂O₅S m/z 355 (M−H)⁻; [α]²⁵ _(D)=−20 (c 0.83, DMSO).

Example 14(5R)-(−)-3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (−)-phenylmethyl4-[4-[(5R)-5-(aminocarbonyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinecarboxylate

Following the general procedure of EXAMPLE 1, Step 1, and makingnon-critical variations but substituting benzyl4-(4-{[benzyloxycarbonyl]amino}-2-fluorophenyl)-1-piperazinecarboxylate(J. Med. Chem. 1996, 39(3), 673-679) for benzyl3-fluoro-4-(4-morpholinyl)phenylcarbamate, the crude1-(phenylmethyl)-4-[4-[(5R)-5-carboxy-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinecarboxylateintermediate is obtained [MS (ESI−) for C₂₂H₂₂N₃O₆F m/z 442 (M−H)⁻] andis used without further purification. This intermediate (1.66 g crude)is taken up in methanol (75 mL), 4 drops of concentrated sulfuric acidare added, and the mixture is stirred at ambient temperature for 19 h.Then, the reaction mixture is concentrated under reduced pressure andchromatographed twice on a Flash 40M 90 g silica gel (32-63 μm)cartridge, eluting with a gradient of methanol/methylene chloride(1/99-2/98). Pooling and concentration of those fractions with anR_(f)=0.64 by TLC (methanol/chloroform, 5/95) provides 740 mg of thephenylmethyl4-[2-fluoro-4-[(5R)-5-(methoxycarbonyl)-2-oxo-3-oxazolidinyl]phenyl]-1-piperazinecarboxylateintermediate [MS (ESI+) for C₂₃H₂₄N₃O₆F m/z 458 (M+H)⁺; 75-80% purity]which is used without further purification. This intermediate is takenup in 2M ammonia in methanol (13 mL), and the resulting mixture isstirred at ambient temperature for 3 h and then concentrated underreduced pressure. The residue is chromatographed on a Flash 40M 90 gsilica gel (32-63 μm) cartridge, eluting with a gradient ofmethanol/methylene chloride (1/99-3/97), and those fractions with anR_(f)=0.20 by TLC (methanol/chloroform, 5/95) are pooled andconcentrated to give the title compound, mp 172-175° C.; MS (ESI+) forC₂₂H₂₃N₄O₅F m/z 443 (M+H)⁺; [α]²⁵ _(D)=−17 (c 1.04, DMSO).

Step 2: Preparation of(5R)-3-[3-fluoro-4-[4-[(phenylmethoxy)acetyl]-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide

A mixture of (−)-phenylmethyl4-[4-[(5R)-5-(aminocarbonyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinecarboxylate(Step 1, 415 mg, 0.938 mmol) and 10% palladium-on-carbon (100 mg, 0.0938mmol) in methanol (45 mL) is shaken under a 45 psi hydrogen atmosphereon a Parr apparatus for 4 h. The catalyst is then removed by filtrationthrough a pad of Celite, and the filtrate is concentrated under reducedpressure to give 290 mg (100%) of the(5R)-3-[(3-fluoro-4-piperazinyl)phenyl]-2-oxo-5-oxazolidinecarboxamideintermediate [MS (ESI+) for C₁₄H₁₇N₄O₃F m/z 309 (M+H)⁺] which is usedwithout further purification. A mixture of this intermediate (240 mg,0.778 mmol) in methylene chloride (7.8 mL) under nitrogen is treatedwith triethylamine (163 μL, 1.17 mmol) followed by benzyloxyacetylchloride (135 μL, 0.856 mmol), and the resulting homogeneous mixture isstirred at ambient temperature for 3 h. The reaction mixture is thendiluted with water (20 mL) and methylene chloride (20 mL), the layersare separated, and the organic phase is washed with saline (10 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to give the crude product which is then chromatographed on aFlash 40M 90 g silica gel (32-63 μm) cartridge, eluting withmethanol/methylene chloride (2.5/97.5). Pooling and concentration ofthose fractions with an R_(f)=0.50 by TLC (methanol/chloroform, 10/90)provides the title compound, ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (s, 1 H),7.61 (s, 1 H), 7.52 (dd, 1 H), 7.36 (m, 4 H), 7.31 (m, 1 H), 7.24 (m, 1H), 7.06 (m, 1 H), 5.01 (dd, 1 H), 4.53 (s, 2 H), 4.25 (m, 3 H), 3.97(dd, 1 H), 3.58 (m, 4 H), 2.96 (m, 4 H); MS (ESI+) for C₂₃H₂₅FN₄O₅ m/z457 (M+H)⁺.

Step 3: Preparation of(5R)-(−)-3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide

A mixture of(5R)-3-[3-fluoro-4-[4-[(phenylmethoxy)acetyl]-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide(Step 2, 260 mg, 0.570 mmol) and 10% palladium-on-carbon (61 mg, 0.0570mmol) in a mixture of methanol (5 mL) and EtOH (23 mL) is shaken under a40 psi hydrogen atmosphere on a Parr apparatus for 22 h. The catalyst isthen removed by filtration through a pad of Celite, rinsing withtetrahydrofuran (200 mL), and the filtrate is concentrated under reducedpressure and triturated with methanol/diethyl ether. Filtration thenprovides the title compound, mp 232-235° C. (dec.); MS (ESI+) forC₁₆H₁₉FN₄O₅ m/z 367 (M+H)⁺; [α]²⁵ _(D)=−20 (c 0.98, DMSO).

Example 15(5R)-(−)-3-[4-(Thiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Step 1: Preparation of 4-(2,6-difluorophenyl)thiomorpholine 1,1-dioxide

Aluminum chloride (310 g, 2.3 mol) is added to chlorobenzene (2.5 L) togive a cloudy green suspension. Vinyl sulfone (230 mL, 2.3 mol) is addedvia funnel, followed by 2,6-difluoroaniline (250 mL, 2.3 mol). The lightbrown solution is heated to 110° C. Upon completion of the reaction, theheat is removed and the black solution is self-cooled to 70° C. Thereaction mixture is then quenched in methylene chloride (4 L) and icewater (5 L), the aqueous phase is extracted with methylene chloride (3L, 2 L, 2 L, 2 L) and the combined organic layers are concentrated,rediluted with branched octane (3 L), and then cooled to 0° C. for 30minutes. The solids are filtered and washed with branched octane (2×500mL) and are then dissolved in methylene chloride (3 L) and loaded onto asilica gel plug (1.8 kg). The column is eluted with dichloromethane (16L) until clear. The methylene chloride solution is concentrated, and thesolids are dissolved in hot ethyl acetate (3 L) followed by the additionof hexanes (900 mL). The black solution is self-cooled to roomtemperature overnight, and the resulting light amber crystal needles arefiltered and washed with hexanes (4×250 mL). The solids are dried underreduced pressure at 50° C. overnight to give the title compound, ¹H NMR(CDCl₃) δ 7.08 (m, 1H), 6.91 (m, 2H), 3.67 (m, 4H), 3.18 (m, 4H).

Step 2: Preparation of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine1,1-dioxide

To a suspension of 4-(2,6-difluorophenyl)thiomorpholine 1,1-dioxide(Step 1, 300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL,ca. 6 mol, fuming, 90%) is added over 30 minutes at ambient temperature.A yellow precipitate forms within minutes and increases over time. Thereaction is kept at room temperature for 18 h and is then poured into 6L of water. After stirring for 2 h, the yellow suspension is filtered.The precipitate is washed with water (1.5 L×3) and ethanol (0.5 L×2) anddried at 50° C. overnight to give the title compound, ¹H NMR (DMSO-d₆) δ8.05 (m, 2H), 3.69 (m, 4H), 3.26 (m, 4H).

Step 3: Preparation of4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluoroaniline

To an autoclave is added 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine1,1-dioxide (Step 2, 7.0 kg, 24 moles, 1.0 eq). Raney Nickel (1.4 kg) isactivated and suspended in tetrahydrofuran (4 L), and the slurry isadded to the autoclave followed by additional tetrahydrofuran (66 L).The mixture is heated at 40° C. under a 40 psi hydrogen atmosphere untilthe reaction is complete. The mixture is then filtered, and the filtrateis directly used in the next step. A small portion of the filtrate canbe concentrated and recrystallized in isopropanol to give the titlecompound in pure form, ¹H NMR (DMSO-d₆) δ 6.17 (m, 2H), 5.35 (s, 2H),3.32 (m, 4H), 3.15 (m, 4H).

Step 4: Preparation of isobutyl4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate

To a 400 L glass-lined reactor containing the4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluoroaniline/tetrahydrofuransolutions (Step 3, 12.6 kg, 48 moles, 1.0 eq) is added a 47% potassiumcarbonate solution (14.1 kg, 48 moles, 1.0 eq). The mixture is heated toapproximately 45° C., and isobutyl chloroformate (7.2 kg, 53 moles, 1.1eq) is added while maintaining a reaction temperature between 45° C. and55° C. The reaction is stirred at 45°-55° C. Once complete, the reactionis quenched by slowly adding water (45 L) over 15 minutes. The reactionmixture is cooled to 25° C. and the phases are separated. Thetetrahydrofuran solution is swapped to an isopropanol (150 L)/water (50L) suspension, and the slurry is slowly cooled to 5° C. The yellowslurry is then filtered and the cake washed with cold isopropanol (2×30L). The yellow solids are dried with 60° C. nitrogen to give the titlecompound, ¹H NMR (CDCl₃) δ 7.02 (m, 2H), 6.81 (s, 1H), 3.95 (d, 2H),3.60 (m, 4H), 3.17 (m, 4H), 1.97 (m, 1H), 0.94 (d, 6H).

Step 5: Preparation of(5R)-(−)-3-[4-(thiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Following the general procedure of EXAMPLE 14, Step 1, and makingnon-critical variations but substituting isobutyl4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate (Step 4)for benzyl4-(4-{[benzyloxycarbonyl]amino}-2-fluorophenyl)-1-piperazinecarboxylateand purifying the final product by trituration and filtration from (10%methanol/chloroform)/diethyl ether, the title compound is obtained, mp245-248° C. (dec.); MS (ESI+) for C₁₄H₁₅F₂N₃O₅S m/z 376 (M+H)⁺; [α]²⁵_(D)=−22 (c 1.00, DMSO).

Example 16(5R)-(−)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide—MethodC

Step 1: Preparation of ethyl(5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate

A solution of 3-fluoro-4-morpholinoaniline (J. Med. Chem. 1996, 39(3),673-679, 0.796 g, 4.0 mmol), ethyl 2(R)-epoxypropanoate (0.696 g, 6.0mmol) and lithium triflate (0.97 g, 6.2 mmol) in acetonitrile (12 mL) isstirred at 50-60° C. overnight. Solvent and excess epoxide is removedunder reduced pressure, and the crude amino alcohol is redissolved indry acetonitrile (40 mL) and 1,1′-carbonyldiimidazole (1.46 g, 9.0 mmol)is added. The mixture is stirred at ambient temperature overnight, andthen the solvent is removed under reduced pressure. The residue ispartitioned between ethyl acetate (70 mL) and 3% aqueous citric acid(100 mL), the layers are separated, and the organic phase is washed with3% aqueous citric acid (3×100 mL), water and saline, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theproduct mixture is then purified by silica gel chromatography, elutingwith ethanol/methylene chloride (2/98), and the appropriate fractionsare pooled and concentrated to give the title compound, MS (ESI+) forC₁₆H₁₉N₂O₅F m/z 339 (M+H)⁺.

Step 2: Preparation of(5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

A mixture of ethyl(5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1, 0.22 g, 0.65 mmol) in 2M ammonia in methanol (5-6 mL) is heatedin a closed vial at 60° C. for approximately 1 h. The resulting mixtureis cooled to ambient temperature and concentrated under reducedpressure, and the crude product is recrystallized from methanol to givethe title compound, MS (ESI+) for C₁₄H₁₆N₃O₄F m/z 310 (M+H)⁺.

Example 17(5R)-(−)-3-[3,5-Difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofbutyl(5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate

A solution of 3,5-difluoro-4-(4-morpholinyl)aniline (See U.S. Pat. No.5,688,792, 2.00 g, 9.34 mmol), butyl 2(R)-glycidate (2.02 g, 14.0 mmol)and lithium triflate (2.18 g, 14.0 mmol) in acetonitrile (37 mL) isstirred at 60° C. under N₂ for 48 h. Solvent is removed under reducedpressure, and the residue is taken up in MeOH/CH₂Cl₂ (5/95, 100 mL),washed with water (2×25 mL) and saline (25 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue isflushed through a Flash 40M 90 g silica gel cartridge with EtOAc/CH₂Cl₂(10/90), and the appropriate fractions are pooled and concentrated togive the amino alcohol intermediate [R_(f)=0.10 by TLC, EtOAc/hexanes(25/75)] which is contaminated with residual starting material. Thisintermediate (2.5 g in two lots) is then dissolved in acetonitrile(total of 70 mL) and treated with 1,1′-carbonyldiimidazole (total of1.69 g, 10.4 mmol, 1.5 equiv.), and the reaction mixtures are stirred atambient temperature for 6 days and then concentrated under reducedpressure. The product mixtures are each taken up in CH₂Cl₂ (50 mL),washed with 0.1M hydrochloric acid (2×20 mL) and saline (10 mL), driedover anhydrous sodium sulfate, concentrated under reduced pressure andchromatographed on a Flash 40M 90 g silica gel cartridge withEtOAc/CH₂Cl₂ (5/95). Those fractions with an R_(f)=0.16 by TLC(EtOAc/hexanes, 25/75) are pooled and concentrated to give the titlecompound, mp 99-100° C.; MS (ESI+) for C₁₈H₂₂N₂O₅F₂ m/z 385 (M+H)⁺.

Step 2: Preparation of(5R)-(−)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Thebutyl(5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1, 350 mg, 0.910 mmol) is treated with 7N ammonia in methanol (9.1mL) under N₂, and the mixture is stirred at ambient temperature for 30mins. The reaction mixture is then concentrated under reduced pressure,and the residue is recrystallized from EtOAc/hexanes to give the titlecompound, mp 181-183° C.; MS (ESI+) for C₁₄H₁₅N₃O₄F₂ m/z 328 (M+H)⁺;[α]²⁵ _(D)−23 (c 0.94, DMSO).

Example 18(5R)-(−)-3-[4-(Thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Step 1: Preparation ofbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

A solution of 4-(4-thiomorpholinyl)aniline (See Med. Chem. Res. 1999,9(3), 149-161, 2.60 g, 13.4 mmol), butyl 2(R)-glycidate (2.89 g, 20.1mmol) and lithium triflate (3.13 g, 20.1 mmol) in acetonitrile (54 mL)is stirred at 60° C. under N₂ for 36 hrs. Solvent is removed underreduced pressure, and the residue is taken up in MeOH/CH₂Cl₂ (5/95, 100mL), washed with water (50 mL) and saline (20 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue isflushed through a Flash 40M 90 g silica gel cartridge with EtOAc/CH₂Cl₂(15/85), and the appropriate fractions are pooled and concentrated togive the amino alcohol intermediate [R_(f)=0.19 by TLC, EtOAc/hexanes(25/75)] which is contaminated with the dialkylated by-product. Thisintermediate (4.25 g) is then dissolved in acetonitrile (125 mL) andtreated with 1,1′-carbonyldiimidazole (3.05 g, 18.8 mmol, 1.5 equiv.),and the reaction mixture is stirred at ambient temperature forapproximately 3 days and then concentrated under reduced pressure. Theproduct mixture is taken up in CH₂Cl₂ (100 mL), washed with 0.1Mhydrochloric acid (3×25 mL) and saline (25 mL), dried over anhydroussodium sulfate, concentrated under reduced pressure and chromatographedon a Flash 40M 90 g silica gel cartridge with EtOAc/CH₂Cl₂ (15/85).Those fractions with an R_(f)=0.57 by TLC (EtOAc/hexanes, 50/50) arepooled and concentrated to give the title compound, mp 95.5-98° C.; MS(ESI+) for C₁₈H₂₄N₂O₄S m/z 365 (M+H)⁺.

Step 2: Preparation ofbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide

A solution ofbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1, 600 mg, 1.65 mmol) in water/acetone (25/75, 32 mL) under N₂ istreated with N-methylmorpholine N-oxide (483 mg, 4.12 mmol) and osmiumtetroxide (2.5 wt % in tBuOH, 1.03 mL, 0.0825 mmol), and the mixture isstirred at ambient temperature for 18 h. The reaction is then treatedwith ½-saturated aqueous sodium bisulfite (20 mL), diluted with water(20 mL) and extracted with CH₂Cl₂ (2×50 mL). The combined organic phaseis washed with saline (20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure, and the product mixture ischromatographed on a Flash 40S 40 g silica gel cartridge withMeOH/CH₂Cl₂ (1/99). Pooling and concentration of those fractions with anR_(f)=0.5 by TLC (MeOH/CHCl₃, 5/95) followed by recrystallization fromEtOAc/hexanes gives the title compound, mp 100-102° C.; MS (ESI+) forC₁₈H₂₄N₂O₆S m/z 397 (M+H)⁺.

Step 3: Preparation of(5R)-(−)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Thebutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide (Step 2, 400 mg, 1.01 mmol) is treated with 7N ammonia inmethanol (10.1 mL) under N₂, and the mixture is stirred at ambienttemperature for 25 mins. The resulting slurry is then diluted withdiethyl ether (5 mL) and filtered to give the title compound, mp226-228° C.; MS (ESI−) for C₁₄H₁₇N₃O₅S m/z 338 (M−H)⁻; [α]²⁵ _(D)−22 (c0.94, DMSO).

Example 20(5R)-(−)-3-[3-Fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Step 1: Preparation ofbutyl(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and makingnon-critical variations but substituting3-fluoro-4-(4-thiomorpholinyl)aniline (See J. Med. Chem. 1996, 39(3),680-685) for 4-(4-thiomorpholinyl)aniline, the title compound isobtained, mp 128-130° C.; MS (ESI+) for C₁₈H₂₃N₂O₄FS m/z 383 (M+H)⁺.

Step 2: Preparation ofbutyl(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 2, and makingnon-critical variations but substitutingbutyl(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 169-171° C. (dec.); MS (ESI+) forC₁₈H₂₃N₂O₆FS m/z 415 (M+H)⁺.

Step 3: Preparation of(5R)-(−)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations but substitutingbutyl(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide (Step 2) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 245-247° C. (dec.); MS(ESI+) for C₁₄H₁₆N₃O₅FS m/z 358 (M+H)⁺; [α]²⁵ _(D)−22 (c 0.92, DMSO).

Example 21(5R)-(−)-3-[3-Fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

Step 1: Preparation ofbutyl(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS-oxide

A solution of sodium periodate (265 mg, 1.24 mmol) in water (5 mL) istreated with a slurry ofbutyl(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 20, Step 1, 450 mg, 1.18 mmol) in methanol (24 mL), and themixture is stirred at ambient temperature for 23 h. The resultingmixture is diluted with water (20 mL) and saline (20 mL) and extractedwith CH₂Cl₂ (2×40 mL), and the combined organic phase is dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue is chromatographed on a Flash 40S 40 g silica gel cartridge,eluting with a gradient of MeOH/CH₂Cl₂ (1/99-2/98), and those fractionswith an R_(f)=0.37 by TLC (MeOH/CHCl₃, 5/95) are pooled and concentratedand the residue recrystallized from EtOAc/hexanes to give the titlecompound, mp 128-129° C.; MS (ESI+) for C₁₈H₂₃N₂O₅FS m/z 399 (M+H)⁺.

Step 2: Preparation of(5R)-(−)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substituting(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide (Step 1) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide and purifying the product by trituration and filtration fromhot acetonitrile, the title compound is obtained, mp 264-266° C. (dec.);MS (ESI+) for C₁₄H₁₆N₃O₄FS m/z 342 (M+H)⁺; [α]²⁵ _(D)−22 (c 0.39, DMSO).

Example 22(5R)-(−)-3-[3,5-Difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

Step 1: Preparation of 4-(2,6-Difluoro-4-nitrophenyl)thiomorpholine

A solution of 3,4,5-trifluoronitrobenzene (5.00 g, 28.24 mmol) inacetonitrile (60 mL) is cooled to 0° C. and treated withN,N-diisopropylethylamine (7.38 mL, 42.35 mmol) followed bythiomorpholine (2.98 mL, 29.65 mmol). The ice bath is removed and thereaction mixture stirred at room temperature under nitrogen forapproximately 24 h, during which additional thiomorpholine (0.1 eq) isadded. The solvent is removed under reduced pressure, and the residue isdiluted with ethyl acetate, washed with 1N hydrochloric acid (until thewashings are acidic), saturated aqueous sodium bicarbonate and saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give the title compound, mp 104-105° C.

Step 2: Preparation of 3,5-difluoro-4-(4-thiomorpholinyl)aniline

A solution of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine (3.00 g, 11.5mmol) in tetrahydrofuran (60 mL) is added to a Parr bottle containing amixture of Raney nickel (1 g) in water (15 mL) under N₂, and thereaction mixture is shaken on a Parr apparatus under a hydrogenatmosphere at 40 psi for 24 hrs. The catalyst is removed by filtrationthrough Celite, rinsing with tetrahydrofuran and water, the filtrate isdiluted with water (50 mL) and EtOAc (50 mL), and the layers areseparated. The organic phase is washed with saline (25 mL), dried overanhydrous magnesium sulfate and concentrated under reduced pressure, andthe resulting oil is chromatographed on a Flash 40M 90 g silica gelcartridge eluting with EtOAc/heptane (15/85). Pooling and concentrationof those fractions with an R_(f)=0.19 by TLC (EtOAc/hexanes, 25/75)gives the title compound, mp 85-86° C.; MS (ESI+) for C₁₀H₁₂N₂F₂S m/z231 (M+H)⁺.

Step 3: Preparation ofbutyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and makingnon-critical variations but substituting3,5-difluoro-4-(4-thiomorpholinyl)aniline (Step 2) for4-(4-thiomorpholinyl)aniline, the title compound is obtained, mp102-103° C.; MS (ESI+) for C₁₈H₂₂N₂O₄F₂S m/z 401 (M+H)⁺.

Step 4: Preparation ofbutyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS-oxide

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingbutyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 3) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 114-116° C.; MS (ESI+) forC₁₈H₂₂N₂O₅F₂S m/z 417 (M+H)⁺.

Step 5: Preparation of(5R)-(−)-3-[3,5-Difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substituting(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide (Step 4) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 273-276° C. (dec.); MS(ESI+) for C₁₄H₁₅N₃O₄F₂S m/z 360 (M+H)⁺; [α]²⁵ _(D)−24 (c 0.96, DMSO).

Example 23(5R)-3-[3-Fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of2-methylpropyl[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate

A solution of2-methylpropyl[3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate(See Org. Proc. Res. Dev. 2001, 5, 80-83, 4.00 g, 12.2 mmol) intrifluoroacetic acid (19 mL, 244 mmol) under N₂ is treated withtriethylsilane (5.85 mL, 36.6 mmol) dropwise, stirred for 1 h, and thenadded dropwise to saturated aqueous potassium carbonate (250 mL) withvigorous stirring. The mixture is extracted with diethyl ether (200 mL),and the organic phase is washed with water (2×50 mL) and saline (50 mL),dried over anhydrous magnesium sulfate and concentrated under reducedpressure. Trituration and filtration from diethyl ether/hexanes or ethylacetate/hexanes gives the title compound, ¹H NMR (CDCl₃, 400 MHz) δ 7.26(m, 1H), 7.11 (t, 1H), 6.97 (m, 1H), 6.59 (bs, 1H), 3.95 (d, 2H), 2.85(m, 3H), 2.68 (m, 2H), 2.09 (m, 2H), 1.98 (m, 1H), 1.84 (m, 2H), 0.96(d, 6H).

Step 2: Preparation of3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)benzenamine

A mixture of2-methylpropyl[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate(Step 1, 2.12 g, 6.81 mmol) in ethylene glycol (25 mL) is treated withaqueous potassium hydroxide (45%, 25.5 g, 204 mmol) with vigorousstirring, and the mixture is heated to 95° C. and stirred at thistemperature for 18 h. The reaction is then cooled to ambient temperatureand diluted with water (50 mL) and CH₂Cl₂ (100 mL), the layers areseparated, and the organic phase is washed with water (50 mL) and saline(20 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product is chromatographed on a Flash 40M 90g silica gel cartridge with a gradient of EtOAc/heptane (15/85-25/75),and those fractions with an R_(f)=0.32 by TLC (EtOAc/hexanes, 25/75) arepooled and concentrated to give the title compound, mp 96-98° C.; MS(ESI+) for C₁₁H₁₄NFS m/z 212 (M+H)⁺.

Step 3: Preparation ofbutyl(5R)-3-[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and makingnon-critical variations but substituting3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)benzenamine (Step 2) for4-(4-thiomorpholinyl)aniline, the title compound is obtained, mp 98-100°C.; MS (ESI+) for C₁₉H₂₄NO₄FS m/z 382 (M+H)⁺.

Step 4: Preparation ofbutyl(5R)-3-[3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingbutyl(5R)-3-[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 3) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,a mixture of the cis and trans sulfoxide products in approximately a 2:1ratio is obtained. Subsequent purification by preparative HPLC(Chiralcel OD column, EtOH eluent) followed by recrystallization fromEtOAc/hexanes provides the title compound, mp 142-145° C.; MS (ESI+) forC₁₉H₂₄NO₅FS m/z 398 (M+H)⁺.

Step 5: Preparation of(5R)-3-[3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substitutingbutyl(5R)-3-[3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 4) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide and purifying the product by trituration and filtration fromhot methanol and acetonitrile, the title compound is obtained, mp279-281° C. (dec.); MS (ESI+) for C₁₅H₁₇N₂O₄FS m/z 341 (M+H)⁺.

Example 24(5R)-3-[3-Fluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofbutyl(5R)-3-[3-fluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingbutyl(5R)-3-[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 23, Step 3) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate, amixture of the cis and trans sulfoxide products in approximately a 2:1ratio is obtained. Subsequent purification by preparative HPLC(Chiralcel OD column, EtOH eluent) followed by recrystallization fromEtOAc/hexanes provides the title compound, mp 133-136° C.; MS (ESI+) forC₁₉H₂₄NO₅FS m/z 398 (M+H)⁺.

Step 2: Preparation of(5R)-3-[3-fluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substitutingbutyl(5R)-3-[3-fluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 201-203° C.; MS (ESI+)for C₁₅H₁₇N₂O₄FS m/z 341 (M+H)⁺.

Example 25(5R)-(−)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Step 1: Preparation of 2-methylpropyl 4-bromophenylcarbamate

A solution of 4-bromoaniline (10.0 g, 58.1 mmol) in tetrahydrofuran (230mL) is treated with sodium bicarbonate (9.77 g, 116.2 mmol) and water(100 mL) followed by isobutyl chloroformate (8.3 mL, 63.9 mmol), and themixture is stirred at ambient temperature for 2 h. The mixture is thendiluted with water (100 mL) and EtOAc (100 mL), the layers areseparated, and the organic phase is washed with water (50 mL) and saline(50 mL), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. Recrystallization of the resulting solid fromEtOAc/hexanes provides the title compound, mp 95-96° C.; MS (ESI−) forCl₁₁H₁₄NO₂Br m/z 270 (M−H)⁻.

Step 2: Preparation of 2-methylpropyl[4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate

A solution of 2-methylpropyl 4-bromophenylcarbamate (Step 1, 10.0 g,36.7 mmol) in anhydrous tetrahydrofuran (184 mL) at −78° C. under N₂ istreated n-butyllithium (1.6M in hexanes, 48.2 mL, 77.1 mmol) dropwiseover 20 mins, and the mixture is stirred at −78° C. for 45 mins. Theresulting slurry is then treated with a solution oftetrahydro-2H-thiopyran-4-one (4.48 g, 38.5 mmol) in anhydroustetrahydrofuran (38 mL) dropwise over 5 mins to give an opaque mixturewhich is allowed to slowly warm to 0° C. with stirring overapproximately 2.5 h. The mixture is then quenched by the slow additionof saturated aqueous ammonium chloride (75 mL), water (75 mL) is added,and the layers are separated. The organic phase is washed with water (50mL) and saline (50 mL), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure, and the crude product isrecrystallized from EtOAc/hexanes to give the title compound, mp150-151° C.; MS (ESI−) for C₁₆H₂₃NO₃S m/z 308 (M−H)⁻.

Step 3: Preparation of2-methylpropyl[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate

Following the general procedure of EXAMPLE 23, Step 1, and makingnon-critical variations but substituting2-methylpropyl[4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate(Step 2) for2-methylpropyl[3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamateand purifying the product by recrystallization from EtOAc/hexanes, thetitle compound is obtained, mp 126-128° C.; MS (ESI−) for C₁₆H₂₃NO₂S m/z292 (M−H)⁻.

Step 4: Preparation of 4-(tetrahydro-2H-thiopyran-4-yl)benzenamine

Following the general procedure of EXAMPLE 23, Step 2, and makingnon-critical variations but substituting2-methylpropyl[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate (Step 3)for2-methylpropyl[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate,the title compound is obtained, mp 103-106° C.; MS (ESI+) for C₁₁H₁₅NSm/z 194 (M+H)⁺.

Step 5: Preparation ofbutyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and makingnon-critical variations but substituting4-(tetrahydro-2H-thiopyran-4-yl)benzenamine (Step 4) for4-(4-thiomorpholinyl)aniline, the title compound is obtained, mp 94-96°C.; MS (ESI+) for C₁₉H₂₅NO₄S m/z 364 (M+H)⁺.

Step 6: Preparation ofbutyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 2, and makingnon-critical variations but substitutingbutyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 5) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 176-179° C.; MS (ESI+) for C₁₉H₂₅NO₆Sm/z 396 (M+H)⁺.

Step 7: Preparation of(5R)-(−)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substitutingbutyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide (Step 6) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 211-212° C.; MS (ESI−)for C₁₅H₁₈N₂O₅S m/z 337 (M−H)⁻; [α]²⁵ _(D)−19 (c 0.95, DMSO).

Example 26(5R)-3-[4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofbutyl(5R)-3-[4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingbutyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 25, Step 5) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,a mixture of the cis and trans sulfoxide products in approximately a 2:1ratio is obtained. Subsequent purification by preparative HPLC(Chiralcel OD column, EtOH eluent) followed by recrystallization fromEtOAc/hexanes provides the title compound, mp 127-130° C.; MS (ESI+) forC₁₉H₂₅NO₅S m/z 380 (M+H)⁺.

Step 2: Preparation of(5R)-3-[4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substitutingbutyl(5R)-3-[4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 269-273° C. (dec.); MS(ESI−) for C₁₅H₁₈N₂O₄S m/z 321 (M−H)⁻.

Example 27(5R)-3-[4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofbutyl(5R)-3-[4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingbutyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 25, Step 5) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,a mixture of the cis and trans sulfoxide products in approximately a 2:1ratio is obtained. Subsequent purification by preparative HPLC(Chiralcel OD column, EtOH eluent) followed by recrystallization fromEtOAc/hexanes provides the title compound, mp 115-117° C.; MS (ESI+) forC₁₉H₂₅NO₅S m/z 380 (M+H)⁺.

Step 2: Preparation of(5R)-3-[4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substitutingbutyl(5R)-3-[4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 174-175° C.; MS (ESI−)for C₁₅H₁₈N₂O₄S m/z 321 (M−H)⁻.

Example 28(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide—Method B

Step 1: Preparation of2-methylpropyl[4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate

Following the general procedure of EXAMPLE 18, Step 2, and makingnon-critical variations but substituting2-methylpropyl[4-(tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate (EXAMPLE 23, Step 1) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, ¹H NMR (CDCl₃) (δ) 7.36 (bd, 1H), 7.14(t, 1H), 6.99 (m, 1H), 6.70 (bs, 1H), 3.95 (d, 2H), 3.14 (m, 4H), 3.07(m, 1H), 2.38 (m, 2H), 2.18 (m, 2H), 1.95 (m,1H), 0.96 (d, 6H).

Step 2: Preparation of(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-hydroxymethyl-2-oxazolidinoneS,S-dioxide

A solution of2-methylpropyl[4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate(Step 1, 2.00 g, 5.82 mmol) in dry tetrahydrofuran at −78° C. under N₂is treated with n-butyllithium (1.6M in hexanes, 3.82 mL, 6.11 mmol)dropwise and stirred at −78° C. for 45 mins. Then, (R)-glycidyl butyrate(0.86 mL, 6.11 mmol) is added dropwise, and the resulting mixture isstirred at −78° C. for 30 mins and at ambient temperature for 2.75 days.The reaction mixture is then quenched with saturated aqueous ammoniumchloride (15 mL), diluted with water (15 mL) and EtOAc (25 mL), and thelayers are separated. The organic phase is diluted with small amounts ofmethylene chloride, methanol and tetrahydrofuran in an attempt todissolve a precipitate that had formed and is then washed with water (20mL) and saline (20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting solid is then dilutedwith hot methanol/EtOAc (1:5, 100 mL), followed by hexanes (150 mL), andfiltered to give the title compound, ¹H NMR (DMSO) δ 7.51 (dd, 1H), 7.37(t, 1H), 7.30 (m, 1H), 5.21 (t, 1H), 4.70 (m, 1H), 4.07 (t, 1H), 3.81(dd, 1H), 3.65 (m, 1H), 3.55 (m, 1H), 3.37 (m, 2H), 3.20 (m, 1H), 3.10(m, 2H), 2.15 (m, 2H), 2.03 (m, 2H).

Step 3: Preparation ofmethyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide

A mixture of ruthenium(III) trichloride (29 mg, 0.139 mmol, 4 mol %),sodium periodate (3.21 g, 15.0 mmol), and sodium dihydrogen phosphatemonohydrate (2.60 g, 18.8 mmol) in water/methylene chloride (10:1, 21mL) is treated with a suspension of(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-hydroxymethyl-2-oxazolidinoneS,S-dioxide (Step 2, 1.20 g, 3.49 mmol) in acetonitrile (35 mL), and theresulting mixture is stirred at ambient temperature for 24 h and is thenadjusted to pH 2 with aqueous hydrochloric acid (1M) and extracted withmethylene chloride (3×100 mL). The combined organic phase is dried overanhydrous sodium sulfate and concentrated under reduced pressure, andthe residue is flushed through a Flash 40M 90 g silica gel cartridgewith a gradient of CH₃CN/CH₂Cl₂ (20/80-40/60) containing 1% formic acid.Those fractions containing the carboxylic acid intermediate (920 mgtotal) are pooled and concentrated, and the white solid is dissolved inmethanol (25 mL) and treated with 3 to 4 drops of concentrated sulfuricacid. The resulting mixture is stirred at ambient temperature for 4 hand is then concentrated under reduced pressure and chromatographed on aFlash 40S 40 g silica gel cartridge, eluting with a gradient ofMeOH/CH₂Cl₂ (1/99-2/98). Pooling and concentration of those fractionswith an R_(f)=0.53 by TLC (MeOH/CH₂Cl₂, 5/95) provides the titlecompound as an amorphous solid, ¹H NMR (CDCl₃) δ 7.50 (dd, 1H), 7.25 (t,1H), 7.15 (m, 1H), 5.09 (dd, 1H), 4.27 (t, 1H), 4.13 (dd, 1H), 3.88 (s,3H), 3.15 (m, 4H), 3.11 (m, 1H), 2.40 (m, 2H), 2.19 (m, 2H).

Step 4: Preparation of(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations but substitutingmethyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide (Step 3) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide and purifying the product by trituration and filtration from(5% MeOH/CH₂Cl₂)/Et₂O, the title compound is obtained, mp 231-234° C.(dec.); MS (ESI−) for C₁₅H₁₇FN₂O₅S m/z 355 (M−H)⁻.

Example 29(5R)-(−)-3-(2,3-Dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-amino-3-methyl-2(3H)-benzothiazolone

A mixture of 6-nitro-3-methyl-2-benzothiazolinone (J. Heterocyclic Chem.1992, 29, 1069-1076, 4.85 g, 23.1 mmol) and 10% palladium-on-carbon (491mg, 0.461 mmol) in a mixture of MeOH (45 mL) and tetrahydrofuran (45 mL)is shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 17h. The catalyst is removed by filtration through a pad of Celite, andthe filtrate is concentrated under reduced pressure and triturated withethyl acetate/hexanes. Filtration then provides the title compound, mp188-190° C.; MS (ESI+) for C₈H₈N₂OS m/z 181 (M+H)⁺.

Step 2: Preparation ofbutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 18, Step 1, and makingnon-critical variations but substituting6-amino-3-methyl-2(3H)-benzothiazolone (Step 1) for4-(4-thiomorpholinyl)aniline, the title compound is obtained, mp 85-87°C.; MS (ESI+) for C₁₆H₁₈N₂O₅S m/z 351 (M+H)⁺.

Step 3: Preparation of(5R)-(−)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Thebutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate(Step 2, 685 mg, 1.95 mmol) is treated with 7N ammonia in MeOH (19 mL)with vigorous stirring, and the mixture is diluted with additional MeOH(20 mL) and tetrahydrofuran (20 mL) and stirred at ambient temperaturefor 1 h. The resulting slurry is concentrated under reduced pressure andthen triturated and filtered from acetone to give the title compound, mp274-276° C. (dec.); MS (ESI−) for C₁₂H₁₁N₃O₄S m/z 292 (M−H)⁻; [α]²⁵_(D)−27 (c 0.98, DMSO).

Example 30(5R)-(−)-3-(2,3-Dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3-ethyl-2(3H)-benzothiazolone

A solution of 6-nitro-2-benzothiazolinone (2.5 g, 12.7 mmol) inanhydrous N,N-dimethylformamide (25 mL) under N₂ is treated with1,8-diazabicyclo[5.4.0]undec-7-ene (2.48 mL, 16.6 mmol) dropwisefollowed by iodoethane (1.22 mL, 15.3 mmol). Following a slightexotherm, the reaction mixture is stirred at ambient temperature for 21h, diluted with water (20 mL) and filtered to give the title compound,mp 200-203° C.

Step 2: Preparation of 6-amino-3-ethyl-2(3H)-benzothiazolone

Following the general procedure of EXAMPLE 29, Step 1, and makingnon-critical variations but substituting6-nitro-3-ethyl-2(3H)-benzothiazolone (Step 1) for6-nitro-3-methyl-2(3H)-benzothiazolone, the title compound is obtained,mp 132-133° C.; MS (ESI+) for C₉H₁₀N₂OS m/z 195 (M+H)⁺.

Step 3: Preparation ofbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate

A solution of 6-amino-3-ethyl-2(3H)-benzothiazolone (Step 2, 790 mg,4.07 mmol), butyl (2R)-glycidate (0.880 g, 6.10 mmol) and lithiumtriflate (0.952 g, 6.10 mmol) in acetonitrile (16 mL) is stirred at 60°C. under N₂ for 18 h. Solvent is removed under reduced pressure, and theresidue is taken up in MeOH/CH₂Cl₂ (5/95, 50 mL), washed with water (50mL) and saline (20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the crude amino alcoholintermediate [R_(f)=0.37 by TLC, EtOAc/hexanes (50/50)] which is carriedforward without further purification. This intermediate is thendissolved in acetonitrile (41 mL) and treated with1,1′-carbonyldiimidazole (0.989 g, 6.10 mmol), and the reaction mixtureis stirred at ambient temperature for approximately 3 days and thenconcentrated under reduced pressure. The product mixture is taken up inMeOH/CH₂Cl₂ (10/90, 50 mL), washed with 0.1M hydrochloric acid (2×30 mL)and saline (20 mL), dried over anhydrous sodium sulfate, concentratedunder reduced pressure and chromatographed on a Flash 40M 90 g silicagel cartridge with a gradient of EtOAc/hexanes (25/75-50/50). Thosefractions with an R_(f)=0.35 by TLC (EtOAc/hexanes, 50/50) are pooledand concentrated to give the title compound, mp 99-102° C.; MS (ESI+)for C₁₇H₂₀N₂O₅S m/z 365 (M+H)⁺.

Step 4: Preparation of(5R)-(−)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Thebutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate(Step 3, 500 mg, 1.37 mmol) is treated with 7N ammonia in MeOH (14 mL)with vigorous stirring, and the mixture is diluted with additional MeOH(20 mL) and stirred at ambient temperature for 30 mins. The resultingslurry is filtered to give the title compound, mp 211-212.5° C.; MS(ESI+) for C₁₃H₁₃N₃O₄S m/z 308 (M+H)⁺; [α]²⁵ _(D)−25 (c 0.92, DMSO).

Example 31(5R)-(−)-3-(2,3-Dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3-isopropyl-2(3H)-benzothiazolone

A stirred solution of 6-nitro-2-benzothiazolinone (5.0 g, 25.5 mmol) inanhydrous N,N-dimethylformamide (51 mL) under N₂ is treated with1,8-diazabicyclo[5.4.0]undec-7-ene (4.96 mL, 33.1 mmol) dropwise.Following a slight exotherm, the reaction mixture is heated up to 50° C.and treated with 2-iodopropane (12.7 mL, 127 mmol). The resultingmixture is quickly heated up to 75° C., stirred at this temperature for40 mins, cooled to ambient temperature and diluted with ice (100 mL) andwater (100 mL). The precipitate is isolated by filtration andrecrystallized from ethyl acetate/hexanes to give the title compound, mp138-142° C.

Step 2: Preparation of 6-amino-3-isopropyl-2(3H)-benzothiazolone

Following the general procedure of EXAMPLE 29, Step 1, and makingnon-critical variations but substituting6-nitro-3-isopropyl-2(3H)-benzothiazolone (Step 1) for6-nitro-3-methyl-2(3H)-benzothiazolone, the title compound is obtained,mp 146-148° C.

Step 3: Preparation ofmethyl(5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate

A vigorously stirred slurry of 6-amino-3-isopropyl-2(3H)-benzothiazolone(Step 2, 2.90 g, 13.9 mmol) and methyl (2R)-glycidate (1.49 g, 14.6mmol) in anhydrous acetonitrile (7 mL) under N₂ is heated up to 70° C.,lithium triflate (2.28 g, 14.6 mmol) is added, and the resultinghomogeneous mixture is heated up to rapid reflux (95-100° C. heatingbath) and monitored by HPLC. After 1 h, solvent is removed under reducedpressure, and the residue is taken up in MeOH/CH₂Cl₂ (5/95, 50 mL),washed with water (50 mL) and saline (25 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to give the crudeamino alcohol intermediate. This intermediate is then dissolved inacetonitrile (70 mL) and treated with 1,1′-carbonyldiimidazole (3.38 g,20.9 mmol), and the reaction mixture is stirred at ambient temperatureovernight and then concentrated under reduced pressure. The residue istaken up in CH₂Cl₂ (100 mL), washed with 0.1M hydrochloric acid (2×50mL) and saline (50 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Trituration and filtration fromMeOH then affords the title compound, mp 161-162° C.; MS (ESI+) forC₁₅H₁₆N₂O₅S m/z 337 (M+H)⁺.

Step 4: Preparation of(5R)-(−)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations but substitutingmethyl(5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate(Step 3) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 183-184.5° C.; MS (ESI+)for C₁₄H₁₅N₃O₄S m/z 322 (M+H)⁺; [α]²⁵ _(D)−25 (c 0.90, DMSO).

Example 32(5R)-(−)-N-Methyl-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Thebutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) is treated with 2N methylaminein MeOH (8.6 mL) with vigorous stirring, and the mixture is diluted withadditional MeOH (10 mL) and stirred at ambient temperature for 1 h. Theresulting slurry is filtered to give the title compound, mp 264-267° C.;MS (ESI+) for C₁₃H₁₃N₃O₄S m/z 308 (M+H)⁺; [α]²⁵ _(D)−44 (c 0.92, DMSO).

Example 33(5R)-(−)-N-Ethyl-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32 and making non-criticalvariations but substituting 2M ethylamine in MeOH for 2M methylamine inMeOH, the title compound is obtained, mp 224.5-226° C.; MS (ESI−) forC₁₄H₁₅N₃O₄S m/z 320 (M−H)⁻; [α]²⁵ _(D)−46 (c 0.89, DMSO).

Example 34 (5R)-(−)-N-(2-Hydroxyethyl)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

A solution ofbutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) in acetonitrile (3.4 mL) istreated with ethanolamine (103 μL, 1.71 mmol) and stirred at ambienttemperature for 18 h. Solvent is removed under reduced pressure, and thecrude product is triturated and filtered from hot ethyl acetate to givethe title compound, mp 217-219° C.; MS (ESI+) for C₁₄H₁₅N₃O₅S m/z 338(M+H)⁺; [α]²⁵ _(D)−43 (c 0.99, DMSO).

Example 35(5R)-N-(2-Fluoroethyl)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

A solution ofbutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 29, Step 2, 985 mg, 2.81 mmol) in pyridine (5.5 mL) in athick-walled, screw-cap vial is treated with fluoroethylaminehydrochloride (2.20 g, 22.1 mmol), and the stirred reaction mixture isplaced in an oil bath maintained at 90° C. for 24 h. The mixture is thencooled to ambient temperature, diluted with CH₂Cl₂ (50 mL), washed with0.2 M hydrochloric acid (25 mL portions, until the washings are at pH<2)and saline (25 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure, and the residue is chromatographed on a Flash40M 90 g silica gel cartridge with MeOH/CH₂Cl₂ (1/99-2.5/97.5). Thosefractions with an R_(f)=0.32 by TLC (MeOH/CHCl₃, 5/95) are pooled andconcentrated and the residue triturated and filtered from MeOH to givethe title compound, mp 201-203° C.; MS (ESI−) for C₁₄H₁₄N₃O₄FS m/z 338(M−H)⁻.

Example 36(5R)-(−)-N-Methyl-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

Thebutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 30, Step 3, 300 mg, 0.823 mmol) is treated with 2N methylaminein MeOH (8.2 mL), and the mixture is stirred at ambient temperature for1 h. The resulting slurry is diluted with Et₂O (10 mL) and filtered togive the title compound, mp 227-229° C.; MS (ESI+) for C₁₄H₁₅N₃O₄S m/z322 (M+H)⁺; [α]²⁵ _(D)−43 (c 0.93, DMSO).

Example 37(5R)-(−)-N-Methyl-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide

The methyl(5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 31, Step 3, 2.89 g, 8.59 mmol) istreated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirredat ambient temperature for 45 mins and then filtered to give the titlecompound, mp 172-173.5° C.; MS (ESI+) for C₁₅H₁₇N₃O₄S m/z 336 (M+H)⁺;[α]²⁵ _(D)−43 (c 0.98, DMSO).

Example 38(5R)-(−)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3-methyl-2(3H)-benzoxazolone

Following the general procedure of EXAMPLE 30, Step 1, and makingnon-critical variations but substituting 6-nitro-2(3H)-benzoxazolone (J.Heterocyclic Chem. 1992, 29, 1069-1076) for 6-nitro-2-benzothiazolinoneand iodomethane for iodoethane, the title compound is obtained, mp183-185° C.

Step 2: Preparation of 6-amino-3-methyl-2(3H)-benzoxazolone

Following the general procedure of EXAMPLE 29, Step 1, and makingnon-critical variations but substituting6-nitro-3-methyl-2(3H)-benzoxazolone (Step 1) for6-nitro-3-methyl-2(3H)-benzothiazolone and using a 2- to 3-hour reactiontime, the title compound is obtained, mp 151-153° C.; MS (ESI+) forC₈H₈N₂O₂ m/z 165 (M+H)⁺.

Step 3: Preparation ofbutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate

A solution of 6-amino-3-methyl-2(3H)-benzoxazolone (Step 2, 1.00 g, 6.09mmol), butyl 2(R)-glycidate (1.32 g, 9.14 mmol) and lithium triflate(1.43 g, 9.14 mmol) in acetonitrile (24 mL) is stirred at 65° C. underN₂ for 6 h and then at ambient temperature over the weekend. Solvent isremoved under reduced pressure, and the residue is taken up inMeOH/CH₂Cl₂ (5/95, 50 mL), washed with water (20 mL) and saline, driedover anhydrous sodium sulfate and concentrated under reduced pressure togive the crude amino alcohol intermediate [MS (ESI+) for C₁₅H₂₀N₂O₅ m/z309 (M+H)⁺]. This intermediate is then dissolved in acetonitrile (61 mL)and treated with 1,1′-carbonyldiimidazole (1.48 g, 9.13 mmol), and thereaction mixture is stirred at ambient temperature for 18 h and thenconcentrated under reduced pressure. The product mixture is taken up inCH₂Cl₂ (50 mL), washed with 0.1M hydrochloric acid (2×30 mL) and saline(20 mL), dried over anhydrous sodium sulfate, concentrated under reducedpressure and chromatographed on a Flash 40M 90 g silica gel cartridgewith EtOAc/CH₂Cl₂ (10/90). Those fractions with an R0.67 by TLC(EtOAc/CH₂Cl₂, 25/75) are pooled and concentrated to give the titlecompound, mp 182-184° C.; MS (ESI+) for C₁₆H₁₈N₂O₆ m/z 335 (M+H)⁺.

Step 4: Preparation of(5R)-(−)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 30, Step 4, and makingnon-critical variations but substitutingbutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylateforbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp>260° C.; MS (ESI−) for C₁₂H₁₁N₃O₅ m/z276 (M−H)⁻; [α]²⁵ _(D)−25 (c 0.94, DMSO).

Example 39 (5R)-(−)-3-(2,3-Dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3-ethyl-2(3H)-benzoxazolone

Following the general procedure of EXAMPLE 30, Step 1, and makingnon-critical variations but substituting 6-nitro-2(3H)-benzoxazolone (J.Heterocyclic Chem. 1992, 29, 1069-1076) for 6-nitro-2-benzothiazolinone,the title compound is obtained, mp 133-135° C.

Step 2: Preparation of 6-amino-3-ethyl-2(3H)-benzoxazolone

Following the general procedure of EXAMPLE 29, Step 1, and makingnon-critical variations but substituting6-nitro-3-ethyl-2(3H)-benzoxazolone (Step 1) for6-nitro-3-methyl-2(3H)-benzothiazolone and using a 2- to 3-hour reactiontime, the title compound is obtained, mp 72-74° C.; MS (ESI+) forC₉H₁₀N₂O₂ m/z 179 (M+H)⁺.

Step 3: Preparation ofbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 38, Step 3, and makingnon-critical variations but substituting6-amino-3-ethyl-2(3H)-benzoxazolone (Step 2) for6-amino-3-methyl-2(3H)-benzoxazolone, the title compound is obtained, mp155-157° C.; MS (ESI+) for C₁₇H₂₀N₂O₆ m/z 349 (M+H)⁺.

Step 4: Preparation of(5R)-(−)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 30, Step 4, and makingnon-critical variations but substitutingbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylatefor butyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate, the titlecompound is obtained, mp 234-236° C.; MS (ESI+) for C₁₃H₁₃N₃O₅ m/z 292(M+H)⁻; [α]²⁵ _(D)−23 (c 0.91, DMSO).

Example 40(5R)-(−)-3-(2,3-Dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 2-(isopropylamino)-5-nitrophenol

A solution of 2-amino-5-nitrophenol (2.00 g, 13.0 mmol) in absolute EtOH(52 mL) and acetone (14.3 mL, 195 mmol, 15 equiv.) is treated withsodium cyanoborohydride (408 mg, 6.49 mmol), the pH is adjusted to4.5-5.0 with glacial AcOH, and the mixture is stirred at ambienttemperature for 4 days, during which time additional acetone (2×14.3mL), sodium cyanoborohydride (3×408 mg) and glacial AcOH is added. Thereaction mixture is then readjusted to pH 6, concentrated under reducedpressure, diluted with water (50 mL) and CH₂Cl₂ (75 mL), and the layersare separated. The organic phase is washed with saline (25 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure,and the residue is chromatographed on a Flash 40M 90 g silica gelcartridge with EtOAc/heptane (20/80). Pooling and concentration of thosefractions with an R_(f)=0.59 by TLC (EtOAc/hexanes, 50/50) gives thetitle compound, mp 108-110° C.; MS (ESI+) for C₉H₁₂N₂O₃ m/z 197 (M+H)⁺.

Step 2: Preparation of 6-nitro-3-isopropyl-2(3H)-benzoxazolone

Method A: A homogeneous mixture of 2-(isopropylamino)-5-nitrophenol(Step 1, 1.86 g, 9.48 mmol) and 1,1′-carbonyldiimidazole (2.31 g, 14.2mmol) in anhydrous THF under N₂ is heated up to 60° C. and stirred atthis temperature for 18 h. Solvent is then removed under reducedpressure, and the residue is taken up in CH₂Cl₂ (50 mL), washed with 0.1M hydrochloric acid (2×50 mL) and saline (25 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. Trituration andfiltration from MeOH gives the title compound, mp 175-176.5° C.

Method B: Following the general procedure of EXAMPLE 31, Step 1, andmaking non-critical variations but substituting6-nitro-2(3H)-benzoxazolone (J. Heterocyclic Chem. 1992, 29, 1069-1076)for 6-nitro-2-benzothiazolinone, the title compound is obtained.

Step 3: Preparation of 6-amino-3-isopropyl-2(3H)-benzoxazolone

Following the general procedure of EXAMPLE 29, Step 1, and makingnon-critical variations but substituting6-nitro-3-isopropyl-2(3H)-benzoxazolone (Step 2) for6-nitro-3-methyl-2(3H)-benzothiazolone and using a 2- to 3-hour reactiontime, the title compound is obtained, MS (ESI+) for C₁₀H₁₂N₂O₂ m/z 193(M+H)⁺.

Step 4: Preparation ofbutyl(5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 38, Step 3, and makingnon-critical variations but substituting6-amino-3-isopropyl-2(3H)-benzoxazolone (Step 3) for6-amino-3-methyl-2(3H)-benzoxazolone, the title compound is obtained, mp86-89° C.; MS (ESI+) for C₁₈H₂₂N₂O₆ m/z 363 (M+H)⁺.

Step 5: Preparation of(5R)-(−)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations but substitutingbutyl(5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(Step 4) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 182.5-184° C.; MS (ESI+)for C₁₄H₁₅N₃O₅ m/z 306 (M+H)⁺.

Example 41(5R)-(−)-N-Methyl-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Following the general procedure of EXAMPLE 36 and making non-criticalvariations but substitutingmethyl(5R)-3-[4-(tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide (EXAMPLE 28, Step 3) forbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 180.5-182° C.; MS (ESI+) forC₁₆H₁₉N₂O₅FS m/z 371 (M+H)⁺; [α]²⁵ _(D)−34 (c 0.94, DMSO).

Example 42(5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Thebutyl(5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 17, Step 1) is treated with 2M methylamine in MeOH (0.1 M instarting material), and the reaction mixture is stirred at ambienttemperature for 30 mins and then concentrated under reduced pressure.The residue is purified by radial chromatography [4000 micron silica gelrotor; MeOH/CH₂Cl₂ (3/97) eluent] to give the title compound, mp179-181° C.; MS (ESI+) for C₁₅H₁₇N₃O₄F₂ m/z 342 (M+H)⁺; [α]²⁵ _(D)−40 (c0.95, DMSO).

Example 43(5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

Step 1: Preparation ofmethyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

A vigorously stirred slurry of 3,5-difluoro-4-(4-thiomorpholinyl)aniline(EXAMPLE 22, Step 2, 10.2 mmol) and methyl (2R)-glycidate (1.14 g, 11.2mmol) in anhydrous acetonitrile (5 mL) under N₂ is heated up to 75° C.,lithium triflate (1.74 g, 11.2 mmol) is added, and the resultinghomogeneous mixture is heated up to rapid reflux (95-100° C. heatingbath) and monitored by HPLC. After 2 h, solvent is removed under reducedpressure, and the residue is taken up in MeOH/CH₂Cl₂ (10/90, 60 mL),washed with water (30 mL) and saline (20 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to give the crudeamino alcohol intermediate which is then purified by silica gelchromatography [Flash 40M 90 g cartridge; EtOAc/CH₂Cl₂ (5/95-10/90)eluent]. This intermediate is dissolved in acetonitrile (47 mL) andtreated with 1,1′-carbonyldiimidazole (1.16 g, 7.12 mmol, 1.5 eq.), andthe reaction mixture is stirred at ambient temperature overnight andthen concentrated down to 10-15 mL under reduced pressure and stirredfor an additional 5 days. Solvent is removed under reduced pressure, andthe residue is taken up in CH₂Cl₂ (100 mL), washed with 0.1Mhydrochloric acid (2×25 mL) and saline (25 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct is then chromatographed on a Flash 40M 90 g silica gelcartridge, eluting with EtOAc/CH₂Cl₂ (5/95), and those fractions with anR_(f)=0.53 by TLC (EtOAc/hexanes, 50/50) are pooled and concentrated toafford the title compound, mp 99-101° C.; MS (ESI+) for C₁₅H₁₆N₂O₄F₂Sm/z 359 (M+H)⁺.

Step 2: Preparation ofmethyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS-oxide

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingmethyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) forbutyl(5R)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateand purifying the crude product mixture by recrystallization fromEtOAc/hexanes, the title compound is obtained, mp 123.5-125° C.; MS(ESI+) for C₁₅H₁₆N₂O₅F₂S m/z 375 (M+H)⁺.

Step 3: Preparation of(5R)-(−)-N-methyl-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS-oxide

Following the general procedure of EXAMPLE 36 and making non-criticalvariations but substitutingmethyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS-oxide (Step 2) forbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 237-241° C.; MS (ESI+) forC₁₅H₁₇N₃O₄F₂S m/z 374 (M+H)⁺; [α]²⁵ _(D)−38 (c 0.94, DMSO).

Example 44(5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Step 1: Preparation ofmethyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 2, and makingnon-critical variations but substitutingmethyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 43, Step 1) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateand purifying the crude product mixture by recrystallization fromEtOAc/hexanes, the title compound is obtained, mp 158.5-161° C.; MS(ESI+) for C₁₅H₁₆N₂O₆F₂S m/z 391 (M+H)⁺.

Step 2: Preparation of(5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Following the general procedure of EXAMPLE 36 and making non-criticalvariations but substitutingmethyl(5R)-3-[3,5-difluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide (Step 1) forbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 243-246° C.; MS (ESI−) forC₁₅H₁₇N₃O₅F₂S m/z 388 (M−H)⁺; [α]²⁵ _(D)−37 (c 1.01, DMSO).

Example 45(5R)-3-[3,5-Difluoro-4-(Tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Step 1: Preparation of 1-(3,5-difluorophenyl)-2,5-dimethyl-1H-pyrrole

To the solution of 3,5-difluoroaniline (3.53 g, 26.8 mmol) intoluene/THF (1:1, 60 mL) is added acetonylacetone (3.24 mL, 26.8 mmol)and p-toluenesulfonic acid monohydrate (0.168 g). The reaction mixtureis heated at reflux for 3 h, concentrated under reduced pressure,diluted with CH₂Cl₂ (60 mL), washed with water (3×10 mL) and saline(2×20 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure. Purification by chromatography on a Biotage Flash 40M90 g silica gel cartridge eluting with EtOAc/Hexanes (5/95-10/90)affords the title compound, mp 55-56° C.

Step 2: Preparation of4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2,6-difluorophenyl]tetrahydro-2H-thiopyran-4-ol

To the solution of 1-(3,5-difluorophenyl)-2,5-dimethyl-1H-pyrrole (Step1, 16.7 g, 80.6 mmol) in anhydrous THF (161 mL) at −78° C. under N₂ isadded n-BuLi (1.6 M in hexanes, 51.8 mL, 82.9 mmol) dropwise. Afterstirring at −78° C. for 1 h, the reaction mixture is treated withtetrahydrothiopyran-4-one (5.35 g, 46.1 mmol) in anhydrous THF (46 mL)dropwise and then stirred at −78° C. for 2 h and at 0° C. for 3 h. Thereaction is then quenched by the slow addition of saturated aqueousammonium chloride (50 mL), diluted with H₂O (50 mL) and Et₂O (50 mL) andthe layers are separated. The organic phase is washed with H₂O (50 mL)and saline (50 mL), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure, and the residue is purified bysilica gel chromatography (650 mL, 10-20% EtOAc/Hexanes eluent) to givethe title compound, mp 125-126° C.; MS (ESI+) for C₁₇H₁₉F₂NOS m/z 324(M+H)⁺.

Step 3: Preparation of1-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2,5-dimethyl-1H-pyrrole

A stirred solution of4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2,6-difluorophenyl]tetrahydro-2H-thiopyran-4-ol(Step 2, 1.617 g, 5.00 mmol) and p-toluenesulfonic acid monohydrate(0.107 g) in benzene (20 mL) is heated at reflux using a Dean-Stark trapfor 5 h, during which additional p-toluenesulfonic acid monohydrate(0.342 g) is added. Solvent is then removed under reduced pressure, andthe residue is taken up in CH₂Cl₂ (60 mL), washed with saturated aqueousNaHCO₃ (2×20 mL) and water (3×20 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. Purification bychromatography on a Biotage Flash 40M 90 g silica gel cartridge, elutingwith 2-5% EtOAc/Hexanes, affords the title compound, mp 118-119° C.; MS(ESI+) for C₁₇H₁₇F₂NS m/z 306 (M+H)⁺.

Step 4: Preparation of4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorobenzenamine

To a stirred solution of1-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2,5-dimethyl-1H-pyrrole(0.828 g, 2.71 mmol) in 95% ethanol/THF (10:1, 55 mL) is addedhydroxylamine hydrochloride (3.77 g, 54.2 mmol) and triethylamine (3.8mL, 27.1 mmol). The reaction mixture is heated at reflux for 2 days andthen concentrated under reduced pressure, diluted with CH₂Cl₂ (60 mL),washed with water (3×20 mL), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. Purification by chromatography on aBiotage Flash 40M 90 g silica gel cartridge, eluting with 10-20%EtOAC/Hexanes, affords the title compound, MS (ESI+) for C₁₁H₁₁F₂NS m/z228 (M+H)⁺; ¹H NMR (CDCl_(3,) 400 MHz) δ 6.22 (m, 2 H), 5.91 (m, 1 H),3.83 (m, 2 H), 3.33 (m, 2 H), 2.86 (t, 2 H), 2.53 (m, 2 H).

Step 5: Preparation ofisobutyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]carbamate

To a stirred, biphasic mixture of4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorobenzenamine (Step 4, 3.90g, 17.2 mmol) in THF/water (2:1, 103 mL) is added sodium bicarbonate(2.88 g, 34.3 mmol) followed by isobutyl carbamate (2.45 mL, 18.9 mmol)dropwise. The reaction mixture is stirred at ambient temperature for 7 hand is then concentrated under reduced pressure, diluted with EtOAc (100mL) and H₂O (50 mL), and the layers are separated. The organic phase iswashed with H₂O (25 mL) and saline (25 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Purificationof the residue by chromatography on a Biotage Flash 40M 90 g silica gelcartridge, eluting with 5-10% EtOAc/Hexanes, affords the title compound,mp 136-137° C.; MS (ESI−) for C₁₆H₁₉F₂NO₂S m/z 326 (M−H)⁻.

Step 6: Preparation ofisobutyl[4-(tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]carbamate

Method A: To a stirred solution ofisobutyl[4-(3,6-dihydro-2H-thiopyran-4-yl) -3,5-difluorophenyl]carbamate(Step 5, 5.62 g, 17.2 mmol) in TFA (26.5 mL, 343 mmol) is addedtriethylsilane (8.23 mL, 51.5 mmol), and the mixture is stirred at 70°C. for 2.2 days, during which additional triethylsilane (2×2.74 mL) isadded, and at 40° C. for 2.6 days. The reaction is then cooled toambient temperature, added slowly to saturated aqueous sodiumbicarbonate (300 mL), and extracted with Et₂O (200 mL). The organiclayer is washed with H₂O (2×50 mL) and saline (50 mL), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure,and the residue is recrystallized from EtOAc/hexanes to give the titlecompound, mp 147-149° C.; MS (ESI−) for C₁₆H₂₁F₂NO₂S m/z 328 (M−H)⁻.

Method B: Step A: Preparation of isobutyl 3,5-difluorophenylcarbamateFollowing the general procedure of Step 5, and making non-criticalvariations but substituting 3,5-difluoroaniline for4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluoroaniline, the titlecompound is obtained, mp 71-74° C.; MS (ESI−) for C₁₁H₁₃NO₂F₂ m/z 228(M−H)⁻.

Step B: Preparation ofisobutyl[4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)-3,5-difluorophenyl]carbamate

A stirred solution of isobutyl 3,5-difluorophenylcarbamate (Step A, 10.0g, 43.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (13.7 mL, 87.3mmol) in anhydrous THF (87 mL) at −78° C. under N₂ is treatedn-butyllithium (1.6M in hexanes, 35.8 mL, 89.4 mmol) dropwise over 35mins. The mixture is stirred at −78° C. for 20 mins and is then treatedwith a solution of tetrahydro-2H-thiopyran-4-one (5.32 g, 45.8 mmol) inanhydrous THF (15 mL) dropwise over 10 mins. After 45 mins at −78° C.,the cooling bath is removed and the mixture is allowed to warm toambient temperature and is then quenched by the slow addition ofsaturated aqueous ammonium chloride (50 mL). Water (50 mL) and EtOAc(100 mL) are added, the layers are separated, and the organic phase iswashed with water (100 mL) and saline (50 mL), dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The crudeproduct is triturated and filtered from EtOAc (approx. 25 mL) to removean insoluble impurity, and the filtrate is chromatographed on two Flash40M 90 g silica gel cartridges, eluting with EtOAc/heptane (20/80).Pooling and concentration of those fractions with an R_(f)=0.26 by TLC(EtOAc/hexanes, 25/75) gives the title compound, mp 103-104° C.

Step C: Preparation ofisobutyl[4-(tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]carbamate

Following the general procedure of Step 6, Method A, and makingnon-critical variations but substitutingisobutyl[4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)-3,5-difluorophenyl]carbamate(Step B) for isobutyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]carbamate, the title compound is obtained.

Step 7: Preparation of3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)benzeneamine

Following the general procedure of EXAMPLE 23, step 2, and makingnon-critical variations but substituting ofisobutyl[4-(tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]carbamate(Step 6) for 2-methylpropyl[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate, the title compound is obtained, mp 118-119° C.;MS (ESI−) for C₁₁H₁₃NF₂S m/z 228 (M−H)⁻.

Step 8: Preparation ofbutyl(5R)-3-[3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 17, Step 1, and makingnon-critical variations but substituting3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)benzenamine (Step 7) for3,5-difluoro-4-(4-morpholinyl)aniline, the title compound is obtained,mp 86-89° C.; MS (ESI+) for C₁₉H₂₃NO₄F₂S m/z 400 (M+H)⁺.

Step 9: Preparation ofbutyl(5R)-3-[3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 2, and makingnon-critical variations but substitutingbutyl(5R)-3-[3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 8) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 218-220° C.; MS (ESI+) forC₁₉H₂₃NO₆F₂S m/z 432 (M+H)⁺.

Step 10: Preparation of(5R)-3-[3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamideS,S-dioxide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations but substitutingbutyl(5R)-3-[3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate S,S-dioxide (Step 9) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 243-245° C.; MS (ESI−)for C₁₅H₁₆N₂O₅F₂S m/z 373 (M−H)⁺.

Example 46(5R)-(−)-3-[3,5-Difluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofbutyl(5R)-3-[3,5-difluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingbutyl(5R)-3-[3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 45, Step 8) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,a mixture of the cis and trans sulfoxide products in approximately a 1:1ratio is obtained. Subsequent purification by preparative HPLC(Chiralcel OD column, EtOH eluent) provides the title compound, MS(ESI+) for C₁₉H₂₃NO₅F₂S m/z 416 (M+H)⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.33(m, 2H), 5.34 (m, 1H), 4.35 (m, 1H), 4,16 (m, 3H), 3.18 (m, 1H), 2.92(m, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 1.61 (m, 4H), 1.35 (sext, 2H), 0.89(t, 3H).

Step 2: Preparation of(5R)-(−)-3-[3,5-difluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations, but substitutingbutyl(5R)-3-[3,5-difluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) for butyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 283-285° C. (dec.); MS(ESI+) for C₁₅H₁₆N₂O₄F₂S m/z 359 (M+H)⁺; [α]²⁵ _(D)−20 (c 0.94, DMSO).

Example 47(5R)-(−)-3-[3,5-Difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofbutyl(5R)-3-[3,5-difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 21, Step 1, and makingnon-critical variations but substitutingbutyl(5R)-3-[3,5-difluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 45, Step 8) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate,a mixture of the cis and trans sulfoxide products in approximately a 1:1ratio is obtained. Subsequent purification by preparative HPLC(Chiralcel OD column, EtOH eluent) provides the title compound, MS(ESI+) for C₁₉H₂₃NO₅F₂S m/z 416 (M+H)⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.31(m, 2H), 5.34 (m, 1H), 4.33 (m, 1H), 4.13 (m, 3H), 3.36 (m, 2H), 3.19(m, 1H), 2.82 (m, 2H), 2.01 (m, 4H), 1.60 (m, 2H), 1.33 (sext, 2H), 0.89(t, 3H).

Step 2: Preparation of(5R)-(−)-3-[3,5-difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 17, Step 2, and makingnon-critical variations but substitutingbutyl(5R)-3-[3,5-difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) for butyl(5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylateand purifying the product by silica gel chromatography (2-5% MeOH/CH₂Cl₂eluent), the title compound is obtained, MS (ESI+) for C₁₅H₁₆N₂O₄F₂S m/z359 (M+H)⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.87 (bs, 1H), 7.63 (bs, 1H),7.33 (m, 2H), 5.04 (dd, 1H), 4.24 (t, 1H), 4.00 (dd, 1H), 3.36 (m, 2H),3.19 (m, 1H), 2.82 (m, 2H), 2.05 (m, 4H); [α]²⁵ _(D)−21 (c 0.96, DMSO).

Example 48 (5R)-N-Methyl-3-[3,5-difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 42 and making non-criticalvariations but substitutingbutyl(5R)-3-[3,5-difluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 47, Step 1) forbutyl(5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylateand purifying the product by silica gel chromatography (1.5-3%MeOH/CH₂Cl₂ eluent), the title compound is obtained, MS (ESI+) forC₁₆H₁₈N₂O₄F₂S m/z 373 (M+H)⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 8.40 (m, 1H),7.32 (m, 2H), 5.07 (dd, 1H), 4.24 (t, 1H), 4.00 (dd, 1H), 3.36 (m, 2H),3.19 (m, 1H), 2.82 (m, 2H), 2.65 (d, 3H), 2.05 (m, 4H).

Example 49(5R)-3-[(2R)-2,3-Dihydro-1-formyl-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of (2R)-2,3-dihydro-2-methyl-1H-indol-5-amine

A mixture of benzyl(2R)-5-{[(benzyloxy)carbonyl]amino}-2-methyl-2,3-dihydro-1H-indole-1-carboxylate(PCT/US00/08224; WO00/73301, 3.36 g, 8.07 mmol) and 10%palladium-on-carbon (108 mg) in THF/MeOH (1:1, 60 mL) is shaken on aParr apparatus under a 36 psi hydrogen atmosphere overnight. Thecatalyst is removed by filtration through a pad of Celite, and thefiltrate is concentrated under reduced pressure. Purification bychromatography on a Biotage Flash 40M 90 g silica gel cartridge (1-2%MeOH/CH₂Cl₂) affords the title compound, MS (ESI+) for C₉H₁₂N₂ m/z 149(M+H)⁺.

Step 2: Preparation of(2R)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3-dihydro-2-methyl-1H-indole

To a stirred solution of (2R)-2,3-dihydro-2-methyl-1H-indol-5-amine(Step 1, 0.896 g, 6.05 mmol) in THF (180 mL) is added acetonylacetone(0.732 mL, 6.05 mmol) and p-toluenesulfonic acid (0.008 g). The reactionmixture is stirred at 68° C. for 6 h and then concentrated under reducedpressure, and the residue is purified by chromatography on a BiotageFlash 40M 90 g silica gel cartridge (10% EtOAc/Hexanes eluent) to givethe title compound, MS (ESI+) for C₁₅H₁₈N₂ m/z 227 (M+H)⁺.

Step 3: Preparation of phenylmethyl (2R)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3-dihydro-2-methyl-1H-indole-1-carboxylate

To a stirred solution of(2R)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3-dihydro-2-methyl-1H-indole(Step 2, 0.100 g, 0.442 mmol) in THF/H₂O (8:1, 4.5 mL) is added sodiumbicarbonate (0.072 g, 0.884 mmol) followed by benzyl chloroformate (80μL, 0.53 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30mins and at ambient temperature for 2 h and is then concentrated underreduced pressure. The residue is taken up in CH₂Cl₂ (40 mL), washed withH₂O (2×10 mL) and saline (2×10 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue is purified bychromatography on a Biotage Flash 40S 40 g silica gel cartridge (1%EtOAc/Hexanes) to give the title compound, MS (ESI+) for C₂₃H₂₄N₂O₂ m/z361 (M+H)⁺.

Step 4: Preparation of phenylmethyl(2R)-5-amino-2,3-dihydro-2-methyl-1H-indole-1-carboxylate

To a stirred solution of phenylmethyl(2R)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3-dihydro-2-methyl-1H-indole-1-carboxylate (Step 3, 2.11 g, 5.84mmol) in water/ethanol (1:9, 60 mL) is added triethylamine (6.5 mL, 46.7mmol) and hydroxylamine hydrochloride (6.49 g, 93.4 mmol). The reactionmixture is stirred at 90° C. for 20 h and is then concentrated underreduced pressure. The residue is taken up in CH₂Cl₂ (60 mL) and washedwith H₂O (2×20 mL) and saline (2×20 mL), and the combined aqueous layeris extracted with CH₂Cl₂ (2×20 mL). The combined organic layer is driedover anhydrous sodium sulfate and concentrated under reduced pressure,and the residue is purified by chromatography on a Biotage Flash 40M 90g silica gel cartridge (30-50% EtOAc/Hexanes eluent) to give the titlecompound, MS (ESI+) for C₁₇H₁₈N₂O₂ m/z 283 (M+H)⁺.

Step 5: Preparation of phenylmethyl(2R)-2,3-dihydro-5-[(5R)-5-(methoxycarbonyl)-2-oxo-3-oxazolidinyl]-2-methyl-1H-indole-1-carboxylate

Following the general procedure of EXAMPLE 38, Step 3, and makingnon-critical variations but substituting phenylmethyl(2R)-5-amino-2,3-dihydro-2-methyl -1H-indole-1-carboxylate (Step 4) for6-amino-3-methyl-2(3H)-benzoxazolone and methyl 2(R)-glycidate for butyl2(R)-glycidate, the title compound is obtained, MS (ESI+) for C₂₂H₂₂N₂O₆m/z 433 (M+Na)⁺.

Step 6: Preparation of methyl(5R)-3-[(2R)-2,3-dihydro-1-formyl-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate

A mixture of phenylmethyl(2R)-2,3-dihydro-5-[(5R)-5-(methoxycarbonyl)-2-oxo-3-oxazolidinyl]-2-methyl-1H-indole-1-carboxylate(Step 5, 0.211 g, 0.51 mmol) and 10% palladium-on-carbon (0.006 g) inmethanol/THF (1:1, 10 mL) is shaken on a Parr apparatus under a 36 psihydrogen atmosphere for 4 h. The catalyst is removed by filtrationthrough a pad of Celite, and the filtrate is concentrated under reducedpressure to give themethyl(5R)-3-[2(R)-2,3-dihydro-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate intermediate which is then dissolved in THF (6mL) and treated with triethylamine (142 μL, 1.02 mmol) and1H-benzotriazole-1-carboxaldehyde (0.092 g, 0.56 mmol). The reactionmixture is stirred at room temperature under N₂ for approximately 18 h,during which additional 1H-benzotriazole -1-carboxaldehyde (0.046 g,0.28 mmol) is added, and is then concentrated under reduced pressure.The residue is taken up in CH₂Cl₂ (40 mL) and washed with H₂O (2×20 mL)and saline (2×20 mL). The combined aqueous layer is extracted withCH₂Cl₂ (2×20 mL), and the combined organic layer is dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue ispurified by chromatography on a Biotage Flash 40M 90 g silica gelcartridge (50-100% EtOAc/Hexanes eluent) to give the title compound, MS(ESI+) for C₁₅H₁₆N₂O₅ m/z 305 (M+H)⁺.

Step 7: Preparation of(5R)-3-[(2R)-2,3-Dihydro-1-formyl-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations but substitutingmethyl(5R)-3-[(2R)-2,3-dihydro-1-formyl-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate(Step 6) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 228-230° C.; MS (ESI+)for C₁₄H₁₅N₃O₄ m/z 290 (M+H)⁺.

Example 50 (5R)-3-[(2R)-2,3-Dihydro-1-(hydroxyacetyl)-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofmethyl(5R)-3-[(2R)-2,3-dihydro-1-[(phenylmethoxy)acetyl]-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 49, Step 6, and makingnon-critical variations but substituting benzyloxyacetyl chloride for1H-benzotriazole-1-carboxaldehyde and purifying the product by silicagel chromatography (1-2% MeOH/CH₂Cl₂ eluent), the title compound isobtained, MS (ESI+) for C₂₃H₂₄N₂O₆ m/z 425 (M+H)⁺.

Step 2: Preparation ofmethyl(5R)-3-[(2R)-2,3-dihydro-1-(hydroxyacetyl)-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate

A mixture ofmethyl(5R)-3-[(2R)-2,3-dihydro-1-[(phenylmethoxy)acetyl]-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate(Step 1, 0.301 g, 0.71 mmol) and Pearlman's catalyst (0.032 g) inmethanol (30 mL) is shaken on a Parr apparatus under a 36 psi hydrogenatmosphere for approximately 24 h, during which additional Pearlman'scatalyst (0.044 g) is added. The catalyst is removed by filtrationthrough a pad of Celite, and the filtrate is concentrated under reducedpressure. The residue is purified by chromatography on a Biotage Flash40S silica gel cartridge (2% MeOH(CH₂Cl₂ eluent) to give the titlecompound, MS (ESI+) for C₁₆H₁₈N₂O₆ M/Z 335 (M+H)⁺.

Step 3: Preparation of(5R)-3-[(2R)-2,3-dihydro-1-(hydroxyacetyl)-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 18, Step 3, and makingnon-critical variations but substitutingmethyl(5R)-3-[(2R)-2,3-dihydro-1-(hydroxyacetyl)-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate(Step 2) forbutyl(5R)-3-[4-(thiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylateS,S-dioxide, the title compound is obtained, mp 198-200° C.; MS (ESI+)for C₁₅H₁₇N₃O₅ m/z 320 (M+H)⁺.

Example 51(5R)-(−)-N-Methyl-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32, and making non-criticalvariations but substitutingbutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 38, Step 3) for butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 304-6° C.; MS (ESI−) for C₁₃H₁₃N₃O₅m/z 290 (M−H)⁻; [α]²⁵ _(D)−34 (c 1.03, DMSO).

Example 52(5R)-(−)-N-Methyl-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32, and making non-criticalvariations but substitutingbutyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 39, Step 3) forbutyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 263-5° C.; MS (ESI−) for C₁₄H₁₅N₃O₅m/z 304 (M−H)⁻; [α]²⁵ _(D)−39 (c 0.94, DMSO).

Example 53(5R)-(−)-N-Methyl-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32, and making non-criticalvariations but substitutingbutyl(5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 40, Step 4) for butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 216-8° C.; MS (ESI−) for C₁₅H₁₇N₃O₅m/z 318 (M−H)⁻; [α]²⁵ _(D)−39 (c 0.95, DMSO).

Example 54(5R)-3-[4-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation ofmethyl(5R)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylate

Following the general procedure of EXAMPLE 31, Step 3, and makingnon-critical variations but substituting5,7-dihydro-6-(2-fluoro-4-aminophenyl)-6H-pyrrolo[3,4-b]pyridine (WO01/42242; PCT/US00/21093) for 6-amino-3-isopropyl -2(3H)-benzothiazoloneand purifying the product by silica gel chromatography (20-30%EtOAc/hexanes eluent), the title compound is obtained, mp 239-240° C.(dec.); MS (ESI+) for C₁₈H₁₆N₃O₄F m/z 358 (M+H)⁺.

Step 2: Preparation of(5R)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Themethyl(5R)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylate(Step 1) is suspended in saturated ammonia in methanol (25 mL), stirredat ambient temperature for 4 h and filtered to give the title compound,mp 257° C. (dec.); MS (ESI+) for C₁₇H₁₅N₄O₃F m/z 343 (M+H)⁺.

Example 55(5R)-N-Methyl-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 32, and making non-criticalvariations but substitutingmethyl(5R)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 54, Step 1) for butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate,the title compound is obtained, mp 275° C. (dec.); MS (ESI+) forC₁₈H₁₇N₄O₃F m/z 357 (M+H)⁺.

Example 56(5R)-3-[4-(cis-1-Imino-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)aniline

A suspension of 2.07 g of2-methylpropyl[3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]carbamate(U.S. Pat. No. 6,239,283) in 25 ml ethylene glycol is treated with 5 ml45% aqueous KOH, placed under N₂ and heated with stirring to 90° C. for10 h. The resulting dark brown colored solution is cooled to ambienttemperature, diluted with water and extracted with 5% MeOH/CH₂Cl₂. Theorganic extracts are combined, dried (NaSO₄), filtered and concentratedto give the crude product which is chromatographed over silica geleluting first with 5% MeOH/EtOAc (to remove a non-polar impurity)followed by elution with 3% MeOH/CHCl₃ (+0.1% NH₄OH) to give the titlecompound, TLC (UV) R_(f)=0.40 in 5% MeOH/CHCl₃ (+0.5% NH₄OH); MS (+ESI)for C₁₁H₁₄FNOS m/z 228 (M+H)⁺.

Step 2: Preparation ofmethyl(5R)-3-[3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate

A suspension of 389 mg (1.71 mmole) of3-fluoro-4-(cis-tetrahydro-1-oxido -2H-thiopyran-4-yl)aniline (Step 1)in 2 ml CH₃CN is treated with 372 mg (1.74 mmole) LiOTf and 150 μL (1.72mmole) of (R)-methyl glycidate. This mixture is placed under N₂ andheated to 80° C. with vigorous stirring. After 17 h the reaction iscooled to ambient temperature, diluted with MeOH and then concentratedunder reduced pressure to give crude product which is chromatographedover silica gel eluting with 4% MeOH/CHCl₃ (+0.1% NH₄OH) to give theamino alcohol intermediate [TLC (UV) R_(f)=0.25 in 5% MeOH/CHCl₃ (+0.5%NH₄OH); MS (+ESI) for C₁₅H₂₀FNO₄S m/z 330 (M+H)⁺]. A solution of 0.91 g(2.8 mmole, from a different lot) of the amino alcohol intermediate in10 ml CH₃CN under N₂ is treated with 0.63 g (3.9 mmole) of1,1′-carbonyldiimidazole and stirred at ambient temperature for 24 h.The milky suspension is diluted with CH₂Cl₂ and washed with waterseveral times. The washes are extracted with CH₂Cl₂ and the combinedorganic extracts are dried (Na₂SO₄), filtered and concentrated to givethe title compound: TLC (UV) R_(f)=0.21 in 5% MeOH/CHCl₃ (+0.5% NH₄OH);MS (+ESI) for C₁₆H₁₈FNO₅S m/z 356 (M+H)⁺.

Step 3: Preparation of(5R)-3-[4-(cis-1-Imino-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Preparation of the MSH reagent: A solution of ethylO-mesitylsulfonylacetohydroxamate (2.53 g, 8.87 mmole) in 7 ml dioxaneis cooled to 0° C. and treated dropwise with 1.0 ml (11.6 mmole) of 70%HClO₄ over ca. 5 min. The solution is stirred at ice bath temperaturefor 7.5 h and then poured into rapidly stirring ice-cold water (35 ml).Stirring is continued for 30 min and then the white solid is collectedby suction filtration through a polypropylene filter tube, washedseveral times with ice-cold water and dissolved in ice-cold CH₂Cl₂. Thissolution is washed twice with cold water and quickly dried by filtrationthrough a plug of anhydrous K₂CO₃ to give a stock solution of MSH inCH₂Cl₂.

All of the MSH stock solution is added directly to 857 mg (2.41 mmole)ofmethyl(5R)-3-[3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(Step 2) suspended in a minimal amount of CH₂Cl₂, and the resultingmixture is rapidly stirred at ambient temperature. After 33 h a thickmilky suspension forms and the reaction looks complete by TLC [(UV)R_(f)=0.30 in 5% MeOH/CHCl₃ (+0.5% NH₄OH) for sulfoximine intermediate].

The milky suspension is dissolved in MeOH, treated with 10 ml 2.0 MNH₃/MeOH and concentrated under reduced pressure until most of theCH₂Cl₂ has been removed. Another 10 ml 2.0 M NH₃/MeOH is added and thesolution is stirred at ambient temperature for 2 h. Additional NH₃/MeOHreagent is added as necessary until all of the ester has been consumed.The solution is concentrated and the crude product is chromatographedover silica gel, eluting with 7.5% MeOH/CHCl₃, and recrystallized fromMeOH/CHCl₃ to give the title compound, mp 226-227° C.; TLC (UV)R_(f)=0.09 in 5% MeOH/CHCl₃ (+0.5% NH₄OH; MS (+ESI) for C₁₅H₁₈FN₃O₄S m/z356 (M+H)⁺; ¹H NMR (d₆-DMSO) δ 7.87 (s, 1H), 7.63 (s, 1H), 7.50 (m, 1H),7.35 (m, 2H), 5.03 (dd, J₁=9.5 Hz, J₂=5.9 Hz, 1H), 4.27 (t, J=9.3 Hz,1H), 4.01 (dd, J₁=9.3 Hz, J₂=5.9 Hz, 1H), 3.77 (s, 1H), 3.25-3.08 (m,3H), 3.06-2.98 (m, 2H), 2.19-2.06 (m, 2H), 2.01-1.92 (m, 2H).

Example 57(5R)-(−)-3-[3,5-Difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of ethyl2-cyano-2-(4-nitro-2,6-difluorophenyl)propionate

A stirred suspension of anhydrous K₂CO₃ (79.5 g, 575 mmol) in anhydrousDMF (365 mL) is heated to 150° C. and treated with ethyl2-cyanopropionate (71.8 g, 564 mmol) via addition funnel over 20 min.The reaction is allowed to cool gradually to ambient temperature over 90min, and then cooled further (to ca. 12° C.) with a mild ice bath. Theyellow reaction mixture is at this point treated with3,4,5-trifluoronitrobenzene (94.8 g, 535 mmol) via addition funnel over20 min. The deep purple reaction mixture is stirred overnight at ambienttemperature. The deep green reaction mixture is then poured intoice/water (950 mL) and made acidic (from pH 11 to pH 5) with 20% v/vH₂SO₄/H₂O while stirring vigorously and ensuring ample cooling with icebath. The mixture is then chilled in a refrigerator for 2 h. Theamber-brown liquid is extracted with Et₂O (1.2 L), taking care todissolve the large clumps of green-black solid (which accounts for asignificant amount of the product). The ethereal layer is washed withH₂O (250 mL), saturated aqueous NaHCO₃ (2×150 mL), and H₂O (2×150 mL),dried over MgSO₄, and concentrated under reduced pressure. Trituration(cold hexanes) affords the title compound as a pale tan solid in 77%yield; ¹H NMR (400 MHz, CDCl₃) δ 7.86 (m, 2 H), 4.35 (q, 2 H), 2.06 (t,3 H), 1.31 (t, 3 H).

Step 2: Preparation of3-methyl-3-(4-amino-2,6-difluorophenyl)azetidinone

A solution of ethyl 2-cyano-2-(4-nitro-2,6-difluorophenyl)propionate(Step 1, 117.3 g, 413 mmol) in anhydrous THF (1.1 L) is treated with 10%Pd/C (11.73 g) and placed under a hydrogen atmosphere (balloon). Thereaction mixture is stirred at ambient temperature for 67 h underhydrogen, then filtered to remove Pd/C and concentrated under reducedpressure to afford the crude nitrile-aniline intermediate (155 g) as adark brown oil. This crude intermediate is dissolved in absolute EtOH(2.0 L), treated with Raney nickel (240 g of a 50% slurry in H₂O), andsubjected to hydrogenation in a Parr apparatus for 24 h (25-30 psi H₂,ambient temperature). The reaction mixture is then filtered throughCelite (repeated EtOH washings) and concentrated under reduced pressure.Flash column chromatography (eluting with 2-3% MeOH/CH₂Cl₂ and then with4-5% MeOH(NH₃)/CH₂Cl₂) provides the uncyclized amino anilineintermediate (74.2 g, 287 mmol) as a pale amber oil in 70% yield (twosteps). A solution of this amino aniline (36.1 g, 140 mmol) in THF (800mL) is added dropwise to a 0° C. solution of methyl magnesium bromide(220 mL, 3.18 M in Et₂O) in THF (1.32 L). The reaction mixture is thenstirred for 22 h with ice bath expiring, and then the reaction contentsare poured into ice-cold saturated aqueous NH₄Cl (1.8 L). The organicand aqueous layers are separated, and the aqueous layer is extractedwith THF (3×300 mL). All organic layers are combined and concentratedunder reduced pressure. The resulting orange-amber syrup is dissolved inEtOAc (800 mL), washed with H₂O (200 mL) and saline (200 mL), dried overMgSO₄, and concentrated under reduced pressure. Trituration (cold Et₂O)affords the title compound as a pale orange solid in 74% yield; ¹H NMR(400 MHz, DMSO-d₆) δ 7.83 (s, 1 H), 6.16 (d, 2 H), 5.65 (s, 2 H), 3.31(m, 1 H), 3.27 (d, 1 H), 1.51 (s, 3 H); hMS (ESI) calcd forC₁₀H₁₀F₂N₂O+H₁ 213.0839, found 213.0849.

Step 3: Preparation of methyl3-(4-amino-2,6-difluorophenyl)-3-methylazetidine-1-carboxylate

A solution of LiAlH₄ (120.9 mL, 1.0 M in THF) is diluted with THF (117mL) and cooled to 0° C. To this is added a solution of3-methyl-3-(4-amino-2,6-difluorophenyl)azetidinone (Step 2, 8.55 g, 40.3mmol) in THF (177 mL), with gas evolution. The ice bath is removed andthe pale yellow solution is heated to reflux (75° C. oil bath) for 22 h,during which time the reaction becomes a white suspension. After coolingto ambient temperature, the mixture is treated successively with H₂O(4.59 mL), 5 N aqueous NaOH (4.13 mL), and H₂O (16.08 mL). The resultingsuspension is diluted with CHCl₃ and filtered through a pad of Celite,rinsing the Celite with additional CHCl₃. Concentration under reducedpressure followed by purification via silica gel chromatography (elutingwith 5% MeOH(NH₃)/CH₂Cl₂) affords the azetidinyl aniline intermediate(5.80 g, 29.3 mmol) as a golden syrup in 73% yield. A solution of thisintermediate (4.93 g, 24.9 mmol) in CH₂Cl₂ (75 mL) is treated with Et₃N(6.93 mL, 49.7 mmol), cooled to 0° C., and treated with methylchloroformate (2.11 mL, 27.3 mmol) dropwise via syringe. The reaction isstirred for 2 h with ice bath expiring and then diluted with CH₂Cl₂,washed with H₂O and saline, dried over MgSO₄, and concentrated underreduced pressure. Purification of the crude product via silica gelchromatography (eluting with 30% EtOAc/hexane) affords the titlecompound as a deliquescent yellow-white solid in 79% yield; ¹H NMR (400MHz, DMSO-d₆) δ 6.17 (d, 2 H), 5.64 (s, 2 H), 4.15 (m, 2 H), 3.81 (m, 2H), 3.56 (s, 3 H), 1.50 (s, 3 H); HRMS (ESI) calcd for C₁₂H₁₄F₂N₂O₂+H₁257.1101, found 257.1095.

Step 4: Preparation ofmethyl(5R)-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl]-2-oxo-5-oxazolidinecarboxylate

A solution of methyl3-(4-amino-2,6-difluorophenyl)-3-methylazetidine-1-carboxylate (Step 3,4.93 g, 19.2 mmol) in CH₃CN (20 mL) is treated with methyl(2R)-glycidate (1.64 mL, 19.2 mmol) and heated to 50° C. To this stirredsolution is added LiOTf (3.00 g, 19.2 mmol) portionwise, and thereaction mixture is then heated at 100° C. for 4 h. After this time thereaction is allowed to cool to ambient temperature with stirringovernight. The reaction is then diluted with EtOAc and washed with H₂O.The H₂O layer is back-extracted with EtOAc, and organic layers arecombined, dried over MgSO₄, and concentrated under reduced pressure.Purification via flash column chromatography (eluting with 30-40%EtOAc/hexane) affords the hydroxy ester intermediate (4.01 g, 11.2 mmol)as a pale yellow solid in 58% yield. A solution of this hydroxy esterintermediate (3.74 g, 10.4 mmol) in CH₃CN (33 mL) is treated with CDI(2.03 g, 12.5 mmol) and a single crystal of DMAP. After stirring for 7days at ambient temperature, the reaction contents are poured into H₂O(150 mL). The resulting phase is then extracted with EtOAc (3×100 mL),and the combined organic layers are dried over MgSO₄ and concentratedunder reduced pressure. Purification of the crude product via silica gelchromatography (eluting with 35-45% EtOAc/hexane) affords the titlecompound as a white solid in 83% yield; ¹H NMR (400 MHz, DMSO-d₆) δ 7.34(d, 2 H), 5.37 (dd, 1 H), 4.34 (t, 1 H), 4.25 (m, 2 H), 4.18 (dd, 1 H),3.87 (d, 2 H), 3.77 (s, 3 H), 3.57 (s, 3 H), 1.57 (s, 3 H); hMS (ESI)calcd for C₁₇H₁₈F₂N₂O₆+H₁ 385.1211, found 385.1199.

Step 5: Preparation of(5R)-(−)-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

A suspension ofmethyl(5R)-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl]-2-oxo-5-oxazolidinecarboxylate(Step 4, 500 mg, 1.30 mmol) in MeOH (10 mL) is heated at 50° C. toachieve full dissolution, then cooled to 0° C. and treated with NH₃-MeOH(5 mL). The ice bath is removed and the reaction mixture stirred for 10min and then concentrated under reduced pressure. Trituration (Et₂O)affords the title compound as a white solid in 97% yield; ¹H NMR (400MHz, DMSO-d₆) δ 7.88 (s, 1 H), 7.64 (s, 1 H), 7.35 (d, 2 H), 5.05 (dd, 1H), 4.26 (m, 2 H), 4.25 (t, 1 H), 4.01 (dd, 1 H), 3.87 (d, 2 H), 3.56(s, 3 H), 1.57 (s, 3 H); hMS (ESI) calcd for C₁₆H₁₇F₂N₃O₅+H₁ 370.1214,found 370.1206; [α]²⁵ _(D)=−20 (c 0.88, DMSO).

Example 58(5R)-(−)-N-Methyl-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

A suspension ofmethyl(5R)-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 57, Step 4, 500 mg, 1.30 mmol) in MeOH (10 mL) is heated at 50°C. to achieve full dissolution, then cooled to 0° C. and treated withmethylamine (15 mL, 2.0 M in MeOH). The reaction mixture is stirred for20 min at 0° C. and then concentrated under reduced pressure.Trituration (Et₂O) affords the title compound as a white solid in 90%yield; ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, 1 H), 7.35 (d, 2 H), 5.09(dd, 1 H), 4.26 (m, 2 H), 4.25 (t, 1 H), 4.02 (dd, 1 H), 3.86 (d, 2 H),3.56 (s, 3 H), 2.66 (d, 3 H), 1.56 (s, 3 H); hMS (ESI) calcd forC₁₇H₁₉F₂N₃O₅+H₁ 384.1371, found 384.1360; [α]²⁵ _(D)=−35 (c 0.90, DMSO).

Example 59 (5R)-3-(3,4-Dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 4-methyl-7-amino-2H-1,4-benzoxazin-3-one

To a stirred suspension of 4-methyl-7-nitro-2H-1,4-benzoxazin-3-one (DE19802239, 2.43 g, 11.67 mmol) in EtOH (20 mL) and water (10 mL) is addedammonium chloride (6.25 g, 116.70 mmol). To this mixture is added iron(1.95 g, 35.00 mmol) in 3 equal portions. The resulting mixture isheated to 80° C. for 2 h at which time the reaction is cooled to roomtemperature followed by addition of CH₂Cl₂ (100 mL). The resultingmixture is filtered through celite and the filtrate is further dilutedwith water (100 mL). The organic layer is separated followed by furtherextraction of the aqueous phase with CH₂Cl₂ (3×50 mL). The organicphases are combined, dried over Na₂SO₄ and concentrated under reducedpressure, and the product is purified by silica gel columnchromatography (EtOAc) to give the title compound in quantitative yield,MS m/z 179.1 (M+H)⁺.

Step 2: Preparation of(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester

To a stirred solution 4-methyl-7-amino-2H-1,4-benzoxazin-3-one (Step 1,7.24 g, 40.63 mmol) in CH₃CN (75 mL) is added LiOTf (6.97 g, 44.69 mmol)followed by methyl (R)-glycidate (4.55 g, 44.69 mmol). The resultingmixture is heated to 50° C. over night at which time HPLC indicatescomplete consumption of the starting material. The reaction is quenchedby addition of water (300 mL), EtOAc (500 mL) and saline (50 mL). Theorganic phase is separated followed by further extraction of the aqueousphase with EtOAc (3×10 mL). The combined organic phase is dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield crudeamino alcohol intermediate which is passed through a short silica gelcolumn (EtOAc) to remove the polar impurities (material balance: 12.24g). The product obtained above is dissolved in anhydrous CH₃CN (100 mL)followed by addition of CDI (19.74, 121.89 mmol, 3 eq. wrt anilineabove) at ambient temperature. The resulting reaction mixture is stirredovernight at which time it is diluted with 0.1 N HCl (50 mL). Theresulting white precipitate is filtered off, washed with additional 0.1N HCl (25 mL) and water (100 mL) and dried under high vacuum to give thetitle compound (7.68 g, 61% for two steps), MS m/z 307.5 (M+H)⁺.

Step 3: Preparation of(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylicacid methyl ester (Step 2, 2.41 g, 7.87 mmol) in MeOH (25 mL) is added2M NH₃ in MeOH (25 mL, 50 mmol). The resulting clear solution becomesturbid after ˜10 min. This mixture is stirred for 16 h at which time thereaction is diluted with ether (20 mL) and the resulting white solidfiltered off. This white solid is washed with several portion of ether(50 mL) and dried under high vacuum to give the title compound (1.87 g,81%), ¹H NMR (300 MHz, DMSO) δ 7.85 (br s, 1H), 7.60 (br s, 1H),7.31-7.14 (m, 3H), 5.00 (dd, 1H), 4.65 (s, 2H), 4.21 (t, 1H), 3.97 (dd,1H), 3.32 (s, 3H); MS for C₁₄H₁₃N₃O₅ m/z 292.5 (M+H)⁺.

Example 60(5R)-N-Methyl-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred suspension of(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylicacid methyl ester (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (5 mL)is added MeNH₂ (5 mL, 10 mmol, 2 M solution in MeOH). The resultingsolution is stirred for 3 h at room temperature at which time theresulting white precipitate is filtered, washed with additional MeOH (5mL), and dried under high vacuum to give the title compound (153 mg,77%); ¹H NMR (300 MHz, DMSO) δ 8.56 (br t, 1H), 7.50 (d, 1H), 7.41-7.33(m, 2H), 5.23 (dd, 1H), 4.85 (s, 2H), 4.45 (dd, 1H), 4.15 (dd, 1H), 3.45(s, 3H), 2.84 (d, 2H); MS for C₁₄H₁₅N₃O₅ m/z 306.5 (M+H)⁺.

Example 61 (5R)-N-(2-Fluoroethyl)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred suspension of(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylicacid methyl ester (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (7.5mL) is added FCH₂CH₂NH₂.HCl (325 mg, 3.25 mmol). To this resultingsuspension is added triethylamine (453 μL, 3.25 mmol), and the solutionis heated to 55° C. for 5 h followed by stirring for 16 h at roomtemperature. The reaction mixture is then concentrated to dryness underreduced pressure and the residue is purified by silica gel columnchromatography (eluent: EtOAc) to give the title compound (153 mg, 63%);¹H NMR (300 MHz, DMSO) δ 8.68 (br t, 1H), 7.30 (d, 1H), 7.22-7.14 (m,2H), 5.08 (dd, 1H), 4.65 (s, 2H), 4.54 (dd, 1H), 4.38 (t, 1H), 4.26 (t,1H), 3.45 (s, 3H), 3.96 (dd, 1H), 3.50-3.35 (m, 5H); MS for C₁₅H₁₆FN₃O₅m/z 338.5 (M+H)⁺.

Example 62(5R)-3-(3,4-Dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 2-amino-5-nitrobenzenethiol

To a stirred solution of 6-nitrobenzothiazole (30 g, 0.1665 mol) inethanol (500 mL) is added 100% hydrazine hydrate (60.2 mL, 1.931 mol).The mixture is refluxed for 2 h at which time the solution turns red.The reaction is quenched by the addition of ice cold conc. HCl until thered color disappears. The resulting solid is filtered, washed with water(25 mL) and dried under high vacuum to give the title compound as ayellow solid (28.96 g, 84%), MS m/z 171.5 (M+H)⁺.

Step 2: Preparation of 3,4-dihydro-7-nitro-2H-1,4-benzothiazin-3-one

To a stirred suspension of 2-amino-5-nitrobenzenethiol (Step 1, 29 g,139.8 mmol) and potassium carbonate (115.93 g, 838.8 mmol) in dry DMF(150 mL) is added methyl bromoacetate (15.88 mL, 167.8 mmol). Thereaction mixture is heated at 50° C. for 16 h at which time the reactionis quenched with ice and water (50 mL). The precipitate is filtered anddried under high vacuum to give the title compound as a yellow solid(21.69 g, 74%), MS m/z 211.5 (M+H)⁺.

Step 3: Preparation of3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzothiazin-3-one

To a stirred suspension of 3,4-dihydro-7-nitro-2H-1,4-benzothiazin-3-one(Step 2, 4.7 g, 22.3 mmol) and potassium carbonate (3.70 g, 26.8 mmol)in dry DMF (40 mL) in an ice bath is added iodomethane (4.16 mL, 66.8mmol). The reaction mixture is taken out of the ice bath and heated at50° C. for 1-2 h. The resulting mixture is allowed to cool down. Water(35 mL) and ice are added and the precipitate is filtered off and washedwith water (10 mL). The resulting solid is dried under high vacuum togive the title compound as a yellow solid (4.5 g, 90%), MS m/z 225.5(M+H)⁺.

Step 4: Preparation of3,4-dihydro-4-methyl-7-amino-2H-1,4-benzothiazin-3-one

To a stirred solution of3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzothiazin-3-one (4.50 g, 20.07mmol) in EtOH (100 mL) and water (50 mL) is added ammonium chloride(10.76 g, 200.7 mmol). To this mixture is added iron (3.37 g, 60.21mmol) in 3 equal portions. The resulting mixture is heated to 80° C. for2 h at which time the reaction is cooled to room temperature. Thismixture is filtered and the filtrate is concentrated under reducedpressure and extracted with EtOAc (3×50 mL). The organic phase is washedwith water and saline, dried over MgSO₄, and concentrated under reducedpressure to give the title compound (for reference see DE 19802239) as adark brown oil (3.60 g, 93%), MS m/z 195.5 (M+H)⁺.

Step 5: Preparation of(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester

To a stirred solution of3,4-dihydro-4-methyl-7-amino-2H-1,4-benzothiazin-3-one (Step 4, 3.60 g,18.54 mmol) in dry CH₃CN (15 mL) is added LiOTf (3.47 g, 22.24 mmol) and(R)-methyl glycidate (1.9 mL, 22.24 mmol). The resulting mixture isstirred at 100° C. for 4 h at which time the reaction is cooled to roomtemperature and worked up in CH₂Cl₂ (3×60 mL) and water (60 mL). Thecombined organic phase is washed with saline, dried over MgSO₄, andconcentrated under reduced pressure to give a dark oil that is purifiedby column chromatography (25% acetone/CH₂Cl₂) to give the amino alcoholintermediate as a dark yellow oil (3.39 g, 62%, MS m/z 297.5 (M+H)⁺). Toa stirred solution of this intermediate (3.39 g, 11.44 mmol) in dryCH₃CN (15 mL) is added CDI (5.56 g, 34.32 mmol). The resulting mixtureis heated at 50° C. for 30 min at which time the reaction is cooled toroom temperature and concentrated under reduced pressure. The crudeproduct is purified by column chromatography (100% EtOAc) to give thetitle compound as white-yellow solid (3.14 g, 85%), MS m/z 323.5 (M+H)⁺.

Step 6: Preparation of(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred suspension of the(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester (Step 5, 200 mg, 0.6205 mmol) in MeOH (3 mL) is addeda 2.0 M solution of ammonia in MeOH (2.0 mL). This mixture is stirredfor 3 h at which time the reaction is concentrated under reducedpressure, washed with ethyl ether (6 mL) and filtered to give the titlecompound as a white solid (108 mg, 57%), ¹H NMR (300 MHz, DMSO) δ 7.86(s, 1H), 7.63 (d, 2H), 7.47 (dd, 1H), 7.27 (d, 1H), 5.01 (dd, 1H), 4.26(t, 1H), 4.00 (dd, 1H), 3.52 (s, 2H), 3.32 (s, 3H); MS for C₁₃H₁₃N₃O₄SMSm/z 308.5 (M+H)⁺.

Example 63(5R)-N-Methyl-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred suspension of the(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester (EXAMPLE 62, Step 5, 200 mg, 0.6205 mmol) in MeOH (3mL) is added a 2.0 M solution of methylamine in MeOH (2.0 mL). Thismixture is stirred for 30 min at which time the reaction is concentratedunder reduced pressure, washed with ethyl ether (6 mL) and filtered togive the title compound as a white solid (190 mg, 95%), ¹H NMR (300 MHz,DMSO) δ 8.38 (d, 1H), 7.63 (d, 1H), 7.46 (dd, 1H), 7.27 (d, 1H), 5.05(dd, 1H), 4.27 (t, 1H), 4.01 (dd, 1H), 3.52 (s, 2H), 3.32 (s, 3H), 2.65(d, 3H); MS for C₁₄H₁₅N₃O₄SMS m/z 322.5 (M+H)⁺.

Example 64(5R)-3-[3-Fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of N′-(2-fluoro-4-nitrobenzoyl)hydrazinecarboxylicacid tert-butyl ester

N,N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) andO-(7-azabenzotriazol-1-yl)-N,N, N,N′-tetramethyluroniumhexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixturestirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57g, 0.0270 mol) is added in one portion and the reaction stirredovernight at room temperature. The mixture is concentrated and dilutedwith water (100 ml). The resulting precipitate is filtered, washed wellwith water, and dried under vacuum to give the title compound as a whitesolid (4.63 g, 57%), [M+H]⁺=300.

Step 2: Preparation ofN′-(2-fluoro-4-nitro-thiobenzoyl)hydrazinecarboxylic acid tert-butylester

N′-(2-Fluoro-4-nitro-benzoyl)hydrazinecarboxylic acid tert-butyl ester(Step 1, 2.32 g, 7.75 mmol) and Lawesson's reagent (2.35 g, 5.81 mmol)in dioxane (50 ml) are heated at 85° C. overnight. The mixture isevaporated under vacuum and the residue purified by flash columnchromatography (70% dichloromethane/hexane) to give the title compoundas a bright orange solid (2.02 g, 82%), [M+H]⁺=316.

Step 3: Preparation of[(tert-Butoxycarbonylhydrazono)-(2-fluoro-4-nitro-phenyl)methylsulfanyl]aceticacid methyl ester

Triethylamine (1.33 ml, 9.57 mmol) is added dropwise at room temperatureto N′-(2-fluoro-4-nitro-thiobenzoyl)hydrazinecarboxylic acid tert-butylester (Step 2, 2.02 g, 6.38 mmol) and methyl bromoacetate (0.633 ml,6.69 mmol) in DMF (20 ml). The mixture is stirred at room temperaturefor 30 minutes and then concentrated under vacuum. The residue ispurified by flash column chromatography (50% ethyl acetate/hexane) togive the title compound as an oil (2.20 g, 86%), [M+H]⁺=388.

Step 4: Preparation of2-(2-fluoro-4-nitrophenyl)-4H-[1,3,4]thiadiazin-5-one

[(tert-Butoxycarbonylhydrazono)-(2-fluoro-4-nitrophenyl)methylsulfanyl]aceticacid methyl ester (Step 3, 2.00 g, 5.16 mmol) is dissolved in 20%trifluoroacetic acid in dichloromethane and stirred at room temperaturefor 45 minutes. The reaction mixture is evaporated under vacuum to givethe title compound as a yellow solid (1.30 g, 99%), [M+H]⁺=256.

Step 5: Preparation of2-(4-amino-2-fluorophenyl)-4H-[1,3,4]thiadiazin-5-one

2-(2-Fluoro-4-nitrophenyl)-4H-[1,3,4]thiadiazin-5-one (Step 4, 0.964 g,0.00378 mol) is heated in ethanol (20 ml) until dissolved. Water (10 ml)and ammonium chloride (2.02 g, 0.0378 mol) are added and the mixtureheated to 90° C. Iron powder (0.84 g, 0.0151 mol) is added portionwiseand the mixture stirred and heated for 30 minutes. The reaction iscooled and dichloromethane (100 ml) added. The mixture is filtered andthe organic layer separated, washed with saline, dried (MgSO₄) andevaporated to give the title compound as a yellow solid (0.78 g, 92%),[M+H]⁺=226.

Step 6: Preparation of(5R)-3-[3-fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid butyl ester

2-(4-Amino-2-fluorophenyl)-4H-[1,3,4]thiadiazin-5-one (Step 5, 0.71 g,3.15 mmol), butyl (2R)-epoxypropanoate (0.91 g, 6.30 mmol) and lithiumtrifluoromethanesulfonate (0.74 g, 4.73 mmol) in acetonitrile (10 ml)are heated at 90° C. overnight. The reaction is concentrated and theresidue diluted with ethyl acetate, washed with water and saline, dried(MgSO₄) and evaporated. The residue is purified by flash columnchromatography (50% ethyl acetate/hexane) to give the amino alcoholintermediate as an oil (0.99 g, 85%, MS (m/z): [M+H]⁺=370). Phosgene(20% solution in toluene, 0.89 ml, 1.68 mmol) is added dropwise at 0° C.to a portion of this intermediate (0.516 g, 1.40 mmol) and triethylamine(0.29 ml, 2.10 mmol) in dichloromethane (10 ml). The mixture is allowedto warm to room temperature and stirred for an additional hour. Thereaction is washed with 2N aqueous hydrochloric acid and saline, dried(MgSO₄) and evaporated. The residue is purified by flash columnchromatography (50% ethyl acetate/hexane) to give the title compound asa white solid (0.33 g, 60%); MS (m/z): [M+H]⁺=396.

Step 7: Preparation of(5R)-3-[3-fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

3-[3-Fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid butyl ester (Step 6, 0.300 g, 0.758 mmol) is dissolved in 2Mammonia in methanol solution (8 ml) and stirred overnight at roomtemperature. The reaction is concentrated under vacuum and purified byPTLC (10% methanol/CH₂Cl₂) to give the title compound as a white solid(0.22 g, 87%), mp 249-251° C.; ¹H NMR (300 Mhz, CDCl₃) δ 3.59 (s, 2H),4.04 (dd, 1H), 4.30 (t, 1H), 5.05 (dd, 1H), 7.49-7.72 (m, 4H), 7.88 (brs, 1H), 11.63 (s, 1H); MS (m/z) for C₁₃H₁₁FN₄O₄S: [M+H]⁺=339.

Example 65(5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of methyl(2R)-3-{[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]amino}-2-hydroxypropanoate

A solution of 4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluoroaniline(EXAMPLE 15, Step 3, 1.30 g, 5.0 mmol) in acetonitrile (7.5 mL) istreated with lithium triflate (0.60 g, 5.0 mmol) and methyl(2R)-2,3-epoxypropanoate (0.51 g, 0.46 mL, 5.0 mmol) and heated to 70°C. for 2 h. At this time an additional amount (1.5 mmol each) of the tworeagents is added and the mixture stirred for another 7 h at 70° C. Thereaction mixture is then cooled to room temperature, concentrated, andpurified by column chromatography (50→60% ethyl acetate-hexane) toprovide the title compound (1.03 g, 57%), MS (m/z): [M+H]⁺=365; ¹H NMR(300 MHz, CDCl₃): δ 3.04 (d, 1H), 3.15 (m, 4H), 3.31-3.46 (m, 2H),3.47-3.56 (m, 4H), 3.83 (s, 3H), 4.20 (t, 1H), 4.40 (m, 1H), 6.17 (d,2H).

Step 2: Preparation ofmethyl(5R)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxylate

A solution of methyl(2R)-3-{[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]amino}-2-hydroxypropanoate(Step 1, 1.02 g, 2.90 mmol) in CH₂Cl₂ (25 mL) and triethylamine (1.0 g,1.5 mL, 10.5 mmol) is cooled to 0° C. and treated with phosgene (1.94 mLof a 20% solution in toluene, 3.6 mmol). After stirring at roomtemperature for one hour, the reaction mixture is diluted with CH₂Cl₂and washed with dilute NaHCO₃, saline, and dried (MgSO₄), filtered andconcentrated. Chromatography on silica gel (10%acetonitrile-dichloromethane) provides the title compound (0.91 g, 83%),MS (m/z): [M+H]⁺=391; ¹H NMR (300 MHz, CDCl₃): δ 3.16-3.20 (m, 4H), 3.64(m, 4H), 3.88 (s, 3H), 4.06-4.11 (m, 1H), 4.23 (t, 1H), 5.06-5.11 (m,1H), 7.16 (d, 2H).

Step 3: Preparation ofmethyl(5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxylate

A solution ofmethyl(5R)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxylate(Step 2, 0.73 g, 1.87 mmol) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.27 g, 5.6 mmol) indioxane (9 mL) is heated to 100° C. for two days. The solution is cooledand treated with 20 mL of 10% aqueous Na₂SO₃ and stirred for 30 minutes.The solution is then diluted with water and extracted three times withethyl acetate. The combined organic phases are washed with satd NaHCO₃and saline and dried (MgSO₄), filtered and concentrated. The cruderesidue is purified by column chromatography (0→5% ethylether-dichloromethane) to provide the title compound (0.28 g, 38%); ¹HNMR (300 MHz, CDCl₃): δ 3.31-3.35 (m, 2H), 3.89 (s, 3H), 4.00-4.15 (m,3H), 4.25 (t, 1H), 5.11 (m, 1H), 5.45 (d, 1H), 6.54 (d, 1H), 7.29 (d,2H).

Step 4: Preparation of(5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

A solution ofmethyl(5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidine-5-carboxylate(Step 3, 0.090 g, 0.23 mmol) in methanol (2 mL) is treated with asolution of ammonia in methanol (2 mL of a 2.0M solution). The mixtureis stirred for 1.5 h and concentrated. The residual solids are washedwith methanol to provide 75 mg (86%) of the title compound as a whitesolid, MS (m/z) for C₁₄H₁₃F₂N₃O₅S: [M+H]⁺=374; ¹H NMR (300 MHz,d6-DMSO): δ 3.33-3.39 (m, 2H), 3.99-4.06 (m, 3H), 4.26 (t, 1H),5.04-5.09 (m, 1H), 5.48 (d, 1H), 6.93 (d, 1H), 7.50 (d, 2H), 7.65 (s,1H), 7.90 (s, 1H).

Example 66(5R)-3-[4-(2,5-Dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of1-(2,6-difluoro-4-nitrophenyl)-2,5-dihydro-1H-pyrrole

Trifluoronitrobenzene (5 g, 28.2 mmol) and 3-pyrroline (1.95 g, 28.2mmol) are taken up in CH₃CN (70.0 mL) and diisopropylethylamine (5.4 mL,31.02 mmol) and heated to 60° C. for 4 h. The reaction mixture is cooledto room temperature, dissolved in ethyl acetate and washed with 0.1 NHCl, sat. NaHCO₃, water, and saline, and dried (MgSO₄), filtered andconcentrated to provide the title compound (6.2 g, 96%), ¹H NMR (300MHz, CDCl₃): δ 4.64 (s, 4H), 5.85 (s, 2H), 7.71 (d, 2H).

Step 2: Preparation of4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluoroaniline

Ammonium chloride (1.18 g, 22.1 mmol) is added to a mixture of1-(2,6-difluoro-4-nitrophenyl)-2,5-dihydro-1H-pyrrole (Step 1, 0.5 g,2.21 mmol) dissolved in EtOH/water (2:1, 18.0 mL) and heated to reflux.Iron powder (0.37 g, 6.63 mmol) is added in portions over one hour.After refluxing for another 45 min, the reaction mixture is cooled,filtered, and extracted three times with dichloromethane. The organiclayers are washed with saline, dried (MgSO₄) and concentrated to providethe title compound (0.43 g, >95%), MS (m/z): [N+H]⁺=197; ¹H NMR (300MHz, CDCl₃): δ 3.63 (bs, 2H), 4.10 (s, 4H), 5.84 (s, 2H), 6.17 (d, 2H).

Step 3: Preparation of methyl(2R)-3-{[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]amino-2-hydroxypropanoate

Methyl (2R)-2,3-epoxypropanoate (0.34 g, 3.3 mmol) and lithium triflate(0.52 g, 3.3 mmol) are added to a solution of4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluoroaniline (Step 2, 0.43 g, 2.2mmol) in acetonitrile (7.5 mL), and the mixture is heated to 60° C. for16 h. The reaction mixture is then concentrated and the residue purifiedby pTLC (50% EtOAc/hexanes) to provide the title compound (0.30 g, 46%),MS (m/z): [M+H]⁺=299.5; ¹H NMR (300 MHz, CDCl₃): δ 3.34-3.41 (m, 2H),3.77 (s, 3H), 4.08 (s, 4H), 4.35-4.37 (m, 1H), 5.82 (s, 2H), 6.16 (d,2H).

Step 4: Preparation ofmethyl(5R)-3-[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxylate

A solution of methyl(2R)-3-{[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]amino}-2-hydroxypropanoate(Step 3, 0.3 g, 1.0 mmol) in acetonitrile (10.0 mL) is treated with1,1′-carbonyldiimidazole (0.33 g, 2.0 mmol) and stirred at roomtemperature for 16 h. The reaction mixture is concentrated and theresidue taken up in ethyl acetate. This organic solution is washed withdilute citric acid, water, and saline and dried (MgSO₄). Purification bypTLC (50% EtOAc/hexanes) provides the title compound (0.15 g, 46%), MS(m/z): [M+H]⁺=325.5; ¹H NMR (300 MHz, CDCl₃): δ 3.88 (s, 3H), 4.03-4.08(m, 1H), 4.20 (t, 1H), 4.37 (s, 4H), 5.03-5.08 (m, 1H), 5.87 (s, 2H),7.06 (d, 2H).

Step 5: Preparation of(5R)-3-[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

A solution ofmethyl(5R)-3-[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidine-5-carboxylate(Step 4, 0.09 g, 0.28 mmol) in 2.0M ammonia in MeOH (2.8 mL) is heatedto 55° C. for 4 h. The reaction mixture is cooled, concentrated and theresidue purified by pTLC (5% MeOH/CH₂Cl₂) to give the title compound (50mg, 58%); MS for C₁₄H₁₃F₂N₃O₃MS m/z 310.5 (M+H)⁺; ¹H NMR (300 MHz,d₆-DMSO): δ 3.93-3.98 (m, 1H), 4.17-4.25 (m, 5H), 4.97-5.02 (m, 1H),5.93 (s, 2H), 7.27 (d, 2H), 7.61 (s, 1H), 7.85 (s, 1H).

Example 67(5R)-3-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 6-nitro-3,4-dihydro-1H-quinolin-2-one

3,4-Dihydro-2(1H)-quinolinone (1.0 g, 6.70 mmol) is dissolved in 20 mLof concentrated sulfuric acid at −10° C., and then 5 mL of water isadded slowly to the solution. After 5 minutes, 61% nitric acid (0.5 mL,6.70 mmol) is added dropwise to the solution. The reaction mixture turnsfrom yellow to dark red, and eventually solidifies. After 1 hour, water(50 mL) is added slowly at −10° C. and precipitate appears. The solutionis poured into a separatory funnel, extracted with ethyl acetate (20mL×2) and washed with saline (20 mL). The organic layers are collectedand dried over MgSO₄. Solvent is removed and the title compound isobtained as a pale yellow solid (1.0 g, 76%); ¹H NMR (300 MHz, DMSO) δ10.66 (s, 1H), 8.08-8.01 (m, 2H), 6.96 (d, 1H), 2.98 (t, 2H), 2.49 (dd,2H).

Step 2: Preparation of 1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one

To a stirred suspension of 6-nitro-3,4-dihydro-1H-quinolin-2-one (Step1, 990 mg, 5.15 mmol) in DMF (3.0 mL) is added K₂CO₃ (855 mg, 1.2equiv.) followed by MeI (0.64 mL, 2.0 equiv.). The resulting solution isstirred overnight at room temperature. Water (20 mL) is then added andthe reaction mixture is extracted with ethyl acetate (20 mL×2) andwashed with saline (20 mL). The organic layers are collected and driedover MgSO₄. Solvent is removed to yield the title compound as a yellowsolid (956 mg, 90%). ¹H NMR (300 MHz, DMSO) δ 8.16-7.26 (m, 3H), 3.30(s, 3H), 3.00 (t, 2H), 2.61 (m, 2H).

Step 3: Preparation of 6-amino-1-methyl-3,4-dihydro-1H-quinolin-2-one

To a stirred suspension of1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 2, 1.04 g, 5.05mmol) in EtOH (10 mL) and water (5 mL) is added ammonium chloride (2.70g, 10.0 equiv.). To this mixture is added iron powder (0.85 g, 3.0equiv.) in 3 portions. The resulting mixture is heated at reflux for 2 hand then is cooled to room temperature. The resulting mixture isfiltered through celite and the filtrate is further diluted with water(100 mL). The filtrate is extracted with ethyl acetate (2×50 mL) andwashed with saline (100 mL). The organic layers are combined, dried overMgSO₄ and concentrated under reduced pressure to yield the titlecompound as a yellow solid (0.86 g, 97%), MS (m/z): 177.5 [M+H]⁺.

Step 4: Preparation of3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester

To a stirred solution 6-amino-1-methyl-3,4-dihydro-1H-quinolin-2-one(Step 3, 0.86 g, 4.91 mmol) in acetonitrile (5 mL) is added lithiumtriflate (0.77 g, 4.91 mmol) followed by methyl-(R)-glycidate (0.42 mL,4.91 mmol). The resulting mixture is heated at 100° C. for 3 h at whichtime HPLC indicates complete consumption of the starting material. Thereaction is quenched by the addition of water (50 mL), and the reactionmixture is extracted with dichloromethane (50 mL×2). The combinedorganic layer is washed with saline (100 mL), dried over MgSO₄ andconcentrated under reduced pressure, and the resulting crude oil ispurified by silica gel chromatography (20% acetone/CH₂Cl₂) to give theamino alcohol intermediate as a yellow solid (0.72 g). This intermediateis dissolved in anhydrous acetonitrile (3 mL) followed by addition ofCDI (0.95 g, 2.25 equiv.) at room temperature. The resulting reactionmixture is stirred for 1 hour at room temperature. Solvent is removedand the residue is purified by silica gel chromatography (100% EtOAc) togive the title compound as a white solid (0.60 g, 76%), MS (m/z): 305.5[M+H]⁺.

Step 5: Preparation of(5R)-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-oxazolidine-5-carboxylicacid methyl ester (Step 4, 150 mg, 0.49 mmol) in MeOH (1 mL) is added2.0 M NH₃ in MeOH (1 mL, 2.0 mmol). The reaction mixture is then heatedat 50-60° C. until all of the solid disappears. Solvent is removed andthe residue is dissolved in 20% MeOH/CH₂Cl₂ and purified by silica gelchromatography (10% MeOH/CH₂Cl₂) to give the title compound as a whitesolid (120 mg, 84%), ¹H NMR (300 MHz, DMSO) δ 7.85 (br S, 1H), 7.60 (brS, 1H), 7.45-7.08 (m, 3H), 5.01 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H),3.23 (s, 3H), 2.86 (t, 2H), 2.50 (m, 2H); MS for C₁₄H₁₅N₃O₄ m/z 290.5(M+H)⁺.

Example 68(5R)-N-Methyl-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester (EXAMPLE 67, Step 4, 150 mg, 0.49 mmol) in MeOH (2 mL)is added MeNH₂ (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reactionmixture is then stirred for 30 minutes at room temperature. Solvent isremoved and the residue is washed with ether to give the title compoundas a white solid (120 mg, 80%), ¹H NMR (300 MHz, DMSO) δ 8.37 (d, 1H),7.44-7.07 (m, 3H), 5.04 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s,3H), 2.86 (t, 2H), 2.65 (d, 3H), 2.50 (m, 2H); MS for C₁₅H₁₇N₃O₄ m/z304.5 (M+H)⁺.

Example 69(5R)-3-[4-(4-Oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one

To a stirring solution of 4-piperidone monohydrate hydrochloride (258.7g, 1.68 mol) and diisopropylethylamine (590 ml, 3.39 mol) inacetonitrile (2.5 liter) is added 3,4-difluoronitrobenzene (186.3 ml,1.68 mol). The mixture is heated to 80° C. and stirred overnight. Thesolvent is cooled to ambient temperature and removed under reducedpressure. The residue is partitioned between ethyl acetate and 10%aqueous HCl (1.20 liter each). The layers are shaken, and the organiclayer is separated and washed with 10% HCl and saline (800 ml each). Theorganic layer is dried over MgSO₄ and filtered. As the solvent isremoved under reduced pressure a solid begins to precipitate out (˜¼volume). The resulting slurry is cooled to 0-5° C. and filtered toafford 333.7 g of the title compound, ¹H NMR (400 MHz, CDCl₃) δ 2.65 (m,4 H), 3.65 (m, 4 H), 6.98 (m, 1 H), 7.26 (s, 1 H), 8.00 (m, 1 H).

Step 2: Preparation of1-(2-fluoro-4-nitrophenyl)-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine

To a stirred solution of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (Step1, 250 g, 1.05 mol) and triethylamine (223 g, 2.20 mol) in toluene (4.2liter) at 0° C. is slowly added trimethylsilyl trifluoromethanesulfonate(TMS-OTf, 280 g, 1.26 mol) via addition funnel. The stirring iscontinued for 30 min and the mixture allowed to warm to ambienttemperature. Water (5 liter) is added and the aqueous layer extractedwith EtOAc (3×500 ml). The organics are combined, dried over MgSO₄ andthe solvent removed under reduced pressure. Hexane (4×500 ml) is addedand the solvent removed under reduced pressure. At the fourthco-distillation, a slurry forms (˜300 ml). The mixture is cooled to 0°C. and the solids filtered. The filtrate is concentrated to a slurry,cooled and filtered (2^(nd) crop). Solids are combined to give 273.7 g(84%) of the title compound as a yellow solid, ¹H NMR (CDCl₃) δ 0.21 (s,9 H), 2.20 (brs, 2 H), 3.52 (brs, 2 H), 3.62 (brs, 2 H), 4.89 (brs, 1H), 6.65 (t, 1 H), 7.67 (d, 1 H), 7.73 (d, 1 H).

Step 3: Preparation of1-(2-fluoro-4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one

To a stirring solution of1-(2-fluoro-4-nitrophenyl)-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine(Step 2, 100.0 g, 322 mmol) and allyl methyl carbonate (43.6 g, 386mmol) in DMSO (625 ml) at ambient temperature is added Pd(OAc)₂ (7.20 g,32 mmol). The resulting solution is stirred under N₂ at ambienttemperature overnight. H₂O (1 liter) is added and solvent allowed tocool to ambient temperature. The aqueous layer is extracted with EtOAc(2×800 ml), and the combined organic layers are washed with saline (800ml) and dried over MgSO₄. The solvent is removed and the residuerecrystallized from EtOAc/MTBE to afford 53.6 g (70%) of the titlecompound as a yellow solid, ¹H NMR (CDCl₃) δ 2.71 (m, 2 H), 4.06 (m, 2H), 5.41 (d, 1 H), 7.25 (m, 1 H), 7.35 (d, 1 H), 8.08 (m, 2 H).

Step 4: Preparation of1-(4-amino-2-fluorophenyl)-2,3-dihydro-1H-pyridin-4-one

In a 500 ml Parr bottle,1-(2-fluoro-4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 3, 35 g,148.3 mmol), Pd/CaCO₃ (3.5 g, 10 wt %) and acetic acid (17 ml, 297 mmol)are combined in THF (350 ml). The mixture is hydrogenated at 40° C.under 15 psi hydrogen for 6 h at which time the reaction is complete byHPLC. The reaction mixture is filtered through a GF/F filter and thecatalyst cake washed with THF (350 ml). The filtrate is partitionedbetween 500 ml of NaHCO₃ and 500 ml of ethyl acetate. The organic layeris washed again with 500 ml of NaHCO₃. The organic layer is separatedand dried over MgSO₄. The mixture is filtered, and the filtrate isconcentrated under reduced pressure to afford 29.0 g (95% recovery) ofthe title compound, MS (ESI−) for C₁₁H₁₁FN₂O m/z 205.0 (M−H)⁻; ¹H NMR(MeOD) δ 7.37 (d, 1 H), 7.02 (t, 1 H), 6.47 (m, 3 H), 5.07 (d, 1 H),3.84 (t, 2 H), 2.58 (t, 1 H).

Step 5: Preparation of3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenylamino]-2(R)-hydroxypropionicacid ethyl ester

A solution of 1-(4-amino-2-fluorophenyl)-2,3-dihydro-1H-pyridin-4-one(Step 4, 0.412 g, 2.0 mmol) and oxirane-2(R)-carboxylic acid ethyl ester(0.394 g, 3.4 mmol) with lithium triflate (0.360 g, 3.0 mmol) in dryacetonitrile (5.0 mL) is heated at 50-60° C. for 24 h. Volatiles areremoved under vacuum, and the crude material purified by silica gelflash chromatography (eluent: 5% acetone in CH₂Cl₂) to afford the titlecompound (290 mg, 45%) as a viscous yellow oil, MS (m/z): 323 [M+H]⁺.

Step 6: Preparation of5(R)-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

CDI (162.0 mg, 1.0 mmol) is added with stirring to a solution of3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenylamino]-2(R)-hydroxypropionicacid ethyl ester (Step 5, 146.0 mg, 0.45 mmol) in acetonitrile (4.0 mL),and the mixture is stirred at room temperature overnight. Solvent isremoved under vacuum, and the residue partitioned between EtOAc (30 mL)and aq. 3% citric acid (30 mL). The aqueous layer is extracted withEtOAc (2×30 mL), and the combined organic layers are washed with waterand saline and dried (MgSO₄). EtOAc is removed under vacuum to affordthe crude3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid ethyl ester which is used in the next step w/o further purification(MS (m/z): 349 [M+H]⁺). The ester intermediate is taken up in 2Mmethanolic ammonia (8.0 mL, 16.0 mmol), and the resulting solutionheated in a closed vial at 60° C. for 1 h. Volatiles are removed undervacuum, and the crude material purified by silica gel chromatography(eluent: 2% MeOH in CH₂Cl₂) to afford the title compound (55.0 mg, 38%for two steps) as white crystals, MS for C₁₅H₁₄FN₃O₄ m/z 320 (M+H)⁺; ¹HNMR (CD₃CN): δ 2.51 (m, 2 H), 3.89 (m, 2 H), 4.05 (m, 1 H), 4.24 (dd, 1H), 4.97 (m, 1 H), 5.03 (d, 1 H), 6.18 (br. s, 1 H), 6.72 (br. s, 1 H),7.20-7.40 (m, 3 H), 7.57 (d, 1 H).

Example 70(5R)-N-Methyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylicacid ethyl ester (EXAMPLE 69, within Step 6, 120 mg, 0.34 mmol) in MeOH(1 mL) is added MeNH₂ (2 mL, 4.0 mmol, 2.0 M solution in MeOH). Thereaction mixture is stirred for 1 h at room temperature. Solvent isremoved and the residue purified by column chromatography (10%MeOH/CH₂Cl₂) to give the title compound as a pale yellow solid (60 mg,52%), ¹H NMR (300 MHz, DMSO) δ 8.39 (m, 1H), 7.65-7.38 (m, 4H), 5.06(dd, 1H), 4.98 (d, 1H), 4.27 (t, 1H), 4.02 (dd, 1H), 3.87 (t, 2H), 2.65(d, 3H); MS for C₁₆H₁₆FN₃O₄ m/z 334.5 (M+H)⁺.

Example 71(5R)-N-Ethyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylicacid ethyl ester (EXAMPLE 69, within Step 6, 108 mg, 0.31 mmol) in MeOH(1 mL) is added EtNH₂ (2 mL, 4.0 mmol, 2.0 M solution in THF). Thereaction mixture is stirred for 1 h at room temperature. Solvent isremoved and the residue purified by column chromatography (10%MeOH/CH₂Cl₂) to give the title compound as a pale yellow solid (100 mg,93%), ¹H NMR (300 MHz, DMSO) δ 8.46 (t, 1H), 7.65-7.38 (m, 4H), 5.05(dd, 1H), 4.99 (d, 1H), 4.27 (t, 1H), 4.01 (dd, 1H), 3.87 (t, 2H),3.20-3.10 (m, 2H), 1.04 (t, 3H); MS for C₁₇H₁₈FN₃O₄ m/z 348.5 (M+H)⁺.

Example 72 (5R)-3-[4-(4-Oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 1-(4-nitrophenyl)piperidin-4-one

The title compound is prepared following the method described in EXAMPLE69, Step 1, using 4-fluoronitrobenzene (9.5 g, 67.3 mmol) in place of3,4-difluoronitrobenzene. The reaction is performed at 50° C. overnight.Yield: 9.90 g (72%). MS (m/z): 221 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ8.15 (d, 2H), 6.83 (d, 2H), 3.80 (t, 4H), 2.61 (t, 4H).

Step 2: Preparation of 1-(4-Nitrophenyl)-4-(triisopropylsilanyloxy)-1,2,3,6-tetrahydropyridine

The title compound is prepared from 1-(4-nitrophenyl)piperidin-4-one(Step 1, 9.90 g, 45 mmol) following the method described for EXAMPLE 69,Step 2, and purified by silica gel flash column chromatography (gradient0 to 15% EtOAc in hexanes). Yield 9.70 g (57%). MS (m/z): 377 [M+1]⁺; ¹HNMR (300 MHz, DMSO): δ 8.04 (d, 2H), 4.92 (d, 2H), 4.92 (t, 1H), 3.88(br. d, 2H), 3.66 (t, 2H), 2.50-2.20 (m, 2H), 1.97-1.12 (m, 3H), 1.02(d, 18H).

Step 3: 1-(4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one

The title compound is prepared from1-(4-nitrophenyl)-4-(triisopropylsilanyloxy)-1,2,3,6-tetrahydropyridine(Step 2, 2.50 g, 6.65 mmol) following the method described for EXAMPLE69, Step 3. The reaction is performed for 4 h, and the product purifiedby silica gel flash column chromatography (gradient 5% to 60% EtOAc inhexanes). Yield 2.10 g (57%). MS (m/z): 219 [M+1]⁺; ¹H NMR (300 MHz,CDCl,): δ 8.39 (d, 2H), 7.49 (d, 1H), 7.14 (d, 2H), 5.39 (d, 1H), 4.06(t, 4H), 2.72 (t, 4H).

Step 4: Preparation of 1-(4-aminophenyl)-2,3-dihydro-1H-pyridin-4-one

The title compound is prepared from 1-(4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 3, 2.75 g, 12.6 mmol) following the methoddescribed for EXAMPLE 69, Step 4. Yield 2.0 g (84%). MS (m/z): 211(M+Na)⁺.

Step 5: Preparation of(5R)-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid ethyl ester

To a stirred solution of 1-(4-aminophenyl)-2,3-dihydro-1H-pyridin-4-one(Step 4, 550 mg, 2.90 mmol) in acetonitrile (5 mL) is addedethyl-(2R)-2,3-epoxypropanate (563 mg, 4.90 mmol) and LiOTf (522 mg,4.40 mmol). The resulting solution is stirred at 50-60° C. for 22 h atwhich time the reaction mixture is concentrated under reduced pressureand the residue is purified by silica gel chromatography (5% acetone inCH₂Cl₂) to afford the amino alcohol intermediate as an orange-coloredoil (275 mg, 31%, MS (m/z): 305.5 [M+H]⁺). The oil (258 mg, 0.85 mmol)is dissolved in acetonitrile (5 mL) followed by addition of CDI (309.5mg, 1.91 mmol). The resulting reaction mixture is stirred at roomtemperature for 36 h at which time the reaction is concentrated underreduced pressure to dryness. The residue is dissolved in EtOAc (50 mL)and washed with 50% aqueous citric acid solution (50 mL). The aqueousphase is washed with EtOAc (5 mL×2), and the combined organic phase isdried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude product is purified by silica gel chromatography (2% MeOH inCH₂Cl₂) to give the title compound as a yellow solid (260 mg, 92%), MS(m/z): 331.5 [M+H]⁺.

Step 6: Preparation of5(R)-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

(5R)-2-Oxo-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]oxazolidine-5-carboxylicacid ethyl ester (Step 5, 213 mg, 0.64 mmol) is dissolved in 2.0 M NH₃in MeOH (8 mL) in a sealed glass vial. This mixture is heated at 60° C.for 1.25 h at which time the reaction is concentrated under reducedpressure and purified by silica gel column chromatography (using 2% MeOHin EtOAc and 2% MeOH in CH₂Cl₂) to obtain the title compound as a lightyellow solid (85 mg, 44%), ¹H NMR (300 MHz, DMSO) δ 7.85 (br s, 1H),7.73 (d, 1H), 7.60-7.55 (m, 3H), 7.30-7.26 (m, 2H), 5.03-4.97 (m, 2H),4.27 (t, 1H), 4.01-3.93 (m, 3H); MS for C₁₅H₁₅N₃O₄ m/z 302.5 (M+H)⁺.

Example 73(5R)-N-Methyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

The title compound is prepared from(5R)-2-oxo-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]oxazolidine-5-carboxylic acid ethyl ester (EXAMPLE 72, Step5, 250 mg, 0.76 mmol) following the method described for EXAMPLE 70.Yield 130 mg (54%). MS for C₁₆H₁₇N₃O₄ m/z 316.3 (M+H)⁺.

Example 74(5R)-N-Ethyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

The title compound is prepared from(5R)-2-oxo-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]oxazolidine-5-carboxylic acid ethyl ester (EXAMPLE 72, Step5, 50 mg, 0.15 mmol) following the method described for EXAMPLE 71.Yield 27 mg (55%). MS for C₁₇H₁₉N₃O₄ m/z 330.5 (M+H)⁺.

Example 75(5R)-N-(2-Fluoroethyl)-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of(5R)-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid ethyl ester (EXAMPLE 72, Step 5, 226 mg, 0.68 mmol) in MeOH (2 mL)is added triethylamine (0.48 mL, 5.0 equiv.). Then 2-fluoroethylaminehydrochloride (136 mg, 2.0 equiv.) is added to the solution. Thereaction mixture is heated at 50-60° C. for 5 h, followed by stirringovernight at room temperature. Solvent is removed and the residue isdissolved in 20% MeOH/CH₂Cl₂ and purified by column chromatography (10%MeOH/CH₂Cl₂). The title compound is obtained as a yellow solid (100 mg,42%), ¹H NMR (300 MHz, DMSO) δ 8.69 (t, 1H), 7.75-7.27 (m, 5H), 5.09(dd, 1H), 4.98 (d, 1H), 4.55 (t, 1H), 4.39 (t, 1H), 4.29 (t, 1H),4.02-3.93 (m, 3H), 3.51-3.37 (m, 2H), 2.50-2.45 (m, 2H); MS forC₁₇H₁₈FN₃O₄ m/z 348.5 (M+H)⁺.

Example 76(5R)-3-[4-(4-Oxo-3,4-dihydro-1(2H)-pyridinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 1-(2,6-difluoro-4-nitrophenyl)piperidin-4-one

The title compound is prepared following the method described forEXAMPLE 69, Step 1, using 3,4,5-trifluoronitrobenzene (3.00 g, 16.94mmol). Yield 1,71 g, (40%). MS (m/z): 257 [M+1]⁺; ¹H NMR (300 MHz,CDCl₃): δ 7.80 (d, 1H), 3.63 (dd, 4H), 2.59 (dd, 4H).

Step 2: Preparation of1-(2,6-difluoro-4-nitrophenyl)-4-(triisopropylsilanyloxy)-1,2,3,6-tetrahydro-pyridine

The title compound is prepared from1-(2,6-difluoro-4-nitrophenyl)piperidin -4-one (Step 1, 1.73 g, 6.75mmol) following the method described for EXAMPLE 69, Step 2, andpurified by silica gel flash chromatography (0 to 25% EtOAc in hexanes).Yield 2.78 g (quant). ¹H NMR (300 MHz, CDCl₃): δ 7.73 (d, 2H), 4.89-4.86(m, 1H), 3.90-3.87 (m, 2H), 3.50-3.45 (m, 2H), 2.34-2.30 (m, 2H),1.07-0.99 (m, 21H).

Step 3: Preparation of1-(2,6-difluoro-4-nitro-phenyl)-2,3-dihydro-1H-pyridin -4-one

The title compound is prepared from1-(2,6-difluoro-4-nitrophenyl)-4-(triisopropylsilanyloxy)-1,2,3,6-tetrahydropyridine(Step 2, 3.10 g, 7.51 mmol) following the method described in EXAMPLE69, Step 3, in 30 min and purified by silica gel flash chromatography(eluent: 50% EtOAc in hexanes). Yield 1.34 g (70%). MS (m/z): 255[M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.23 (d, 2H), 7.53-7.49 (m, 1H), 5.23(d, 1H), 3.95 (t, 2H), 2.53-2.47 (m, 2H).

Step 4: Preparation of1-(4-amino-2,6-fluorophenyl)-2,3-dihydro-1H-pyridin -4-one

The title compound is prepared from 1-(2,6-difluoro-4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 3, 1.34 g, 5.27 mmol) following themethod described for EXAMPLE 69, Step 4. Yield 1.08 g (91%).

Step 5: Preparation of(5R)-3-[3,5-difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester

To a stirred solution of1-(4-amino-2,6-fluorophenyl)-2,3-dihydro-1H-pyridin -4-one (Step 4, 553mg, 2.46 mmol) in acetonitrile (20 mL) is added by butyl-(R)-glycidate(532 mg, 3.69 mmol) followed by LiOTf (770 mg, 4.93 mmol). The resultingsolution is stirred at 50° C. for 16 h at which time the reaction isquenched by addition of water (20 mL) and extracted with EtOAc (20mL×3). The combined organic phase is dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield crude product that ispassed through a short silica gel column (EtOAc) to give the aminoalcohol intermediate (620 mg; MS (m/z): 369.4 [M+H]⁺) which is usedwithout further purification. To a stirred solution of this intermediatein acetonitrile (20 mL) is added CDI (750 mg, 4.62 mmol). The resultingsolution is stirred at room temperature for 16 h at which time thereaction is quenched by the addition of water (20 mL) and diluted withEtOAc (25 mL). The organic phase is separated followed by extraction ofthe aqueous phase with EtOAc (20 mL×2). The combined organic phase iswashed with water (20 mL) and saline (20 mL), dried over Na₂SO₄ andconcentrated under reduced pressure and the residue is purified bysilica gel chromatography (50% EtOAc in hexane to EtOAc) to give thetitle compound (219 mg, 24% over 2 steps), MS (m/z): 395.6 [M+H]⁺.

Step 6: Preparation of(5R)-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

(5R)-3-[3,5-Difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid butyl ester (Step 5, 200 mg, 0.50 mmol) is dissolved in a 2Msolution of NH₃ in MeOH (4 mL, 8 mmol). The resulting solution isstirred at room temperature for 3 h at which time the reaction mixtureis concentrated under reduced pressure. The residue is washed with etherto give the title compound as an off white solid (139 mg, 82%), ¹H NMR(300 MHz, DMSO) δ 7.89 (br s, 1H), 7.64 (br s, 1H), 7.54-7.38 (m, 3H),5.07-4.98 (m, 2H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H); MS forC₁₅H₁₃F₂N₃O₄ m/z 338.4 (M+H)⁺.

Example 77(5R)-N-Methyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of(5R)-3-[3,5-Difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (EXAMPLE76, Step 5, 132 mg) in MeOH (1 mL) is added MeNH₂ (2 mL, 4.0 mmol, 2.0 Msolution in MeOH). The reaction mixture is then heated at 40-50° C.until all of the solid disappears. Solvent is removed and the residue isdissolved in 20% MeOH/CH₂Cl₂ and purified by silica gel chromatography(10% MeOH/CH₂Cl₂) to give the title compound as a yellow solid (100 mg,76%), ¹H NMR (300 MHz, DMSO) δ 8.40 (m, 1H), 7.52-7.38 (m, 3H), 5.08(dd, 1H), 5.00 (d, 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H), 2.65(d, 3H); MS for C₁₆H₁₅F₂N₃O₄ m/z 352.5 (M+H)⁺.

Example 78(5R)-N-Ethyl-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide

The title compound is prepared from(5R)-3-[3,5-difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylicacid butyl ester (EXAMPLE 76, Step 5, 60 mg) following the methoddescribed for EXAMPLE 71. ¹H NMR (300 MHz, DMSO) δ 8.48 (t, 1H),7.52-7.38 (m, 3H), 5.06 (dd, 1H), 4.99 (d, 1H), 4.26 (t, 1H), 4.01 (dd,1H), 3.79 (t, 2H), 3.20-3.10 (m, 2H), 1.04 (t, 3H); MS for C₁₇H₁₇F₂N₃O₄m/z 366.5 (M+H)⁺.

Example 79(5R)-3-[4-[3,4-Dihydro-4-(hydroxyimino)-1(2H)-pyridinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of5(R)-3-[4-(4-oxo-3,4-dihydro-1(2H)-pyridinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide(EXAMPLE 69, 110 mg, 0.34 mmol) in pyridine (2 mL) is addedhydroxylamine hydrochloride (95 mg, 1.38 mmol). To this mixture is addedMeOH (1 mL) and CH₂Cl₂ (1 mL) and the solution becomes clear. Thissolution is stirred for 16 h at which time it is concentrated underreduced pressure. The residue is purified by silica gel chromatography(2 to 5% MeOH in EtOAc) to give the title compound as a white solid (18mg, 16%) as a mixture of E and Z isomers, ¹H NMR (300 MHz, DMSO) δ 10.32(s, 1H, minor isomer), 10.06 (s, 1H, major isomer), 7.61-7.53 (m, 2H),7.35-7.7.20 (m, 2H), 6.76-6.64 (m, 1H), 5.59 (d, 1H, major isomer), 5.19(d, 1H, minor isomer), 5.04-4.99 (m, 1H), 4.25 (t, 1H), 4.02-3.96 (m,1H), 3.65-3.50 (m, 2H), 2.71-2.66 (m, 2H); MS (ESI+) for C₁₅H₁₅FN₄O₄ m/z335 (M+H)⁺.

Example 80(5R)-3-(2,2-Difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of2,2-difluoro-4-methyl-7-nitro-4H-1,4-benzoxazin-3-one

To a stirred suspension of 2,2-difluoro-7-nitro-4H-1,4-benzoxazin-3-one(WO 99/40094, 2.16 g, 9.38 mmol) in DMF (10 mL) is added K₂CO₃ (1.94 g,14.07 mmol) followed by addition of MeI (0.87 mL, 14.07 mmol). Theresulting solution is stirred over night at room temperature. To thisreaction mixture is added water (50 mL), and the resulting solution isextracted with EtOAc (50 mL×3). The combined organic phases are washedwith water (50 mL) and saline (50 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to give the title compound that ispurified by passing through a short silica gel column with EtOAc (1.3 g,57%), ¹H NMR (300 MHz, DMSO) δ 8.25-8.17 (m, 2H), 7.62 (d, 1H), 3.47 (s,3H).

Step 2: Prepartion of2,2-difluoro-4-methyl-7-amino-4H-1,4-benzoxazin-3-one

To a stirred suspension of2,2-difluoro-4-methyl-7-nitro-4H-1,4-benzoxazin-3-one (Step 1, 1.3 g,5.32 mmol) in EtOH (20 mL) and water (10 mL) is added ammonium chloride(2.85 g, 53.32 mmol). To this mixture is added iron (892 mg, 15.09 mmol)in 3 equal portions. The resulting mixture is heated to 80° C. for 2 hat which time the reaction is cooled to room temperature followed byaddition of CH₂Cl₂ (50 mL). The resulting mixture is filtered throughcelite and the filtrate is further diluted with water (50 mL). Theorganic layer is separated followed by further extraction of the aqueousphase with CH₂Cl₂ (50 mL×3). The combined organic phase is dried overNa₂SO₄ and concentrated under reduced pressure, and the residue ispurified by passing it through a short silica gel column with EtOAc togive the title compound (1.05 g, Quant.), MS (m/z): 215.5 [M+H]⁺.

Step 3: Preparation of(5R)-3-(2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester

To a stirred solution2,2-difluoro-7-amino-4-methyl-4H-1,4-benzoxazin-3-one (Step 2, 1.05 g,4.90 mmol) in acetonitrile (25 mL) is added LiOTf (841 mg, 5.39 mmol)followed by methyl-(R)-glycidate (549 mg, 5.39 mmol). The resultingmixture is heated to 50° C. over night at which time HPLC indicatescomplete consumption of the starting material. The reaction is quenchedby addition of water (50 mL), EtOAc (100 mL) and saline (50 mL). Theorganic phase is separated followed by further extraction of the aqueousphase with EtOAc (20 mL×3). The combined organic phase is dried overNa₂SO₄, filtered and concentrated under reduced pressure, and theresidue is passed through a short silica gel column (EtOAc) to removethe polar impurities from the amino alcohol intermediate (MS (m/z):317.5 [M+H]⁺). This intermediate is dissolved in anhydrous acetonitrile(20 mL) followed by addition of CDI (1.58 g, 9.80 mmol, 2 eq. wrtaniline above) at room temperature. The resulting reaction mixture isstirred overnight at which time it is diluted with 0.1 N HCl (10 mL).The resulting pale yellow precipitate is filtered off, washed withadditional 0.1 N HCl (25 mL) and water (100 mL) and dried under highvacuum to give the title compound (1.30 g, 77% for two steps), MS (m/z):342.7 [M+H]⁺.

Step 4: Preparation of(5R)-3-(2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of(5R)-3-(2,2-difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester(Step 3, 50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M NH₃ in MeOH (2 mL,4 mmol). The resulting mixture is stirred for 16 h at which time thereaction is concentrated under reduced pressure and purified by silicagel chromatography (EtOAc) to give the title compound as a light yellowsolid (21 mg, 44%), ¹H NMR (300 MHz, DMSO) δ 7.86 (br s, 1H), 7.61 (d,2H), 7.52-7.41 (m, 2H), 5.02 (dd, 1H), 4.28 (t, 1H), 4.02 (dd, 1H), 3.42(s, 3H); MS for C₁₃H₁₁F₂N₃O₅ m/z 328.5 (M+H)⁺.

Example 81 (5R)-N-Methyl-3-(2,2-difluoro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred solution of(5R)-3-(2,2-Difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester(EXAMPLE 80, Step 3, 50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M MeNH₂in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h atwhich time a precipitate forms. The mixture is heated until it becomesclear, and the product is allowed to crystallize at room temperature inthe form of white needles. The crystals are separated, washed with etherand dried under high vacuum at 50° C. to give the title compound (25 mg,50%), ¹H NMR (300 MHz, DMSO) δ 8.38 (br d, 1H), 7.60 (d, 1H), 7.51-7.41(m, 2H), 5.06 (dd, 1H), 4.29 (t, 1H), 4.03 (dd, 1H), 3.41 (s, 3H), 2.65(d, 2H); MS for C₁₄H₁₃F₂N₃O₅ m/z 342.5 (M+H)⁺.

Example 82(5R)-3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 8-fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one

8-Fluoro-3,4-dihydro-1H-quinolin-2-one [prepared according to theprocedure found in EP0524846] (2.62 g, 0.0159 mol) is dissolved inconcentrated sulfuric acid (20 ml) and cooled to −5° C. Nitric acid(70%, 1.02 ml, 0.0159 mol) is added dropwise and the reaction stirred at−5° C. for 20 minutes. The mixture is poured onto ice and the resultingprecipitate collected by filtration, washed well with water, and driedunder vacuum. Purification by flash column chromatography (30% ethylacetate/hexane) gives the title compound as a light yellow solid (2.50g, 75%); [M+H]⁺=211.

Step 2: Preparation of8-fluoro-1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one

8-Fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 3.13 g, 0.0149mol) and iodomethane (1.39 ml, 0.0223 mol) in DMF (25 ml) are stirred atroom temperature overnight. The reaction is diluted with water and theresulting precipitate collected by filtration, washed well with water,and dried under vacuum to give the title compound as an orange solid(2.97 g, 89%); ¹H NMR (300 MHz, CDCl₃) δ 2.56-2.61 (m, 2H), 2.99-3.04(m, 2H), 3.32 (s, 3H), overlapping 8.06 (s, 1H) and 8.08 (dd, 1H);[M+H]⁺=225.

Step 3: Preparation of6-amino-8-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

8-Fluoro-1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 2, 2.28 g,0.0102 mol) is heated in ethanol (75 ml) until dissolved. Water (25 ml)and ammonium chloride (5.46 g, 0.102 mol) are added and the mixtureheated to 90° C. Iron powder (2.27 g, 0.0407 mol) is added portionwiseand the mixture stirred and heated for 30 minutes. The reaction iscooled and dichloromethane (200 ml) added. The mixture is filtered andthe organic layer separated, washed with saline, dried (MgSO₄) andevaporated to give the title compound as a yellow solid (1.98 g, 99%);[M+H]⁺=195.

Step 4: Preparation of3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-2-hydroxypropionic acid methyl ester

6-Amino-8-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (Step 3, 2.25 g,0.0116 mol), methyl (2R)-glycidate (1.18 g, 0.0116 mol) and lithiumtrifluoromethanesulfonate (1.81 g, 0.0116 mol) in acetonitrile (10 ml)are heated at 90° C. overnight. The reaction is concentrated and theresidue diluted with ethyl acetate, washed with water and saline, dried(MgSO₄) and evaporated. The residue is purified by flash columnchromatography (50% ethyl acetate/hexane) to give the title compound asa yellow solid (2.13 g, 62%); MS (m/z): [M+H]⁺=297.

Step 5: Preparation of(5R)-3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester

Phosgene (20% solution in toluene, 4.07 ml, 7.69 mmol) is added dropwiseat 0° C. to3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-2-hydroxypropionicacid methyl ester (Step 4, 1.81 g, 6.41 mmol) and triethylamine (2.23ml, 16.0 mmol) in dichloromethane (25 ml). The mixture is allowed towarm to room temperature and stirred for an additional hour. Thereaction is washed with 2N aqueous hydrochloric acid and saline, dried(MgSO₄) and evaporated. The residue is purified by flash columnchromatography (50% ethyl acetate/hexane) to give the title compound asa white solid (1.71 g, 83%); MS (m/z): [M+H]⁺=323.

Step 6: Preparation of(5R)-3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide

3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester (Step 5, 0.300 g, 9.31 mmol) is dissolved in 2Mammonia in methanol solution (8 ml) and stirred overnight at roomtemperature. The resulting precipitate is filtered, washed withmethanol, and dried under vacuum to give the title compound as a whitesolid (0.185 g, 65%), mp 260-2° C.; ¹H NMR (300 MHz, CDCl₃) δ 2.48-2.52(m, 2H), 2.85-2.89 (m, 2H), 3.28 (d, 3H), 4.00 (dd, 1H), 4.24 (t, 1H),5.03 (dd, 1H), 7.27 (s, 1H), 7.46 (dd, 1H), 7.62 (br s, 1H), 7.87 (br s,1H); MS for C₁₄H₁₄FN₃O₄ m/z 308 (M+H)⁺.

Example 83(5R)-N-Methyl-3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide

3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester (EXAMPLE 82, Step 5, 0.300 g, 9.31 mmol) is dissolvedin 2M methylamine in methanol solution (8 ml) and stirred overnight atroom temperature. The resulting precipitate is filtered, washed withmethanol, and dried under vacuum to give the title compound as a whitesolid (0.145 g, 48%), mp 264-5° C.; ¹H NMR (300 MHz, CDCl₃) δ 2.47-2.52(m, 2H), 2.64 (d, 3H), 2.84-2.89 (m, 2H), 3.27 (d, 3H), 4.00 (dd, 1H),4.24 (t, 1H), 5.06 (dd, 1H), 7.26 (s, 1H), 7.46 (dd, 1H), 8.39 (d, 1H);MS for C₁₅H₁₆FN₃O₄ m/z 322 (M+H)⁺.

Example 843-(4-Methyl-3-thioxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of(5R)-3-(3,4-dihydro-4-methyl-3-thioxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester

To a stirred suspension of the(5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester (EXAMPLE 62, Step 5, 1.26 g, 3.907 mmol) in drydioxane (25 mL) is added Lawesson's reagent (2.37 g, 5.861 mmol). Thisreaction mixture is heated at 70-80° C. for 1.5-2 h at which time thereaction is cooled to room temperature and concentrated under reducedpressure. The residue is washed with EtOAc (15 mL×3), sonicated andfiltered to give the title compound as a yellow solid (1.18 g, 89%), MS(m/z): 339.5 [M+H]⁺.

Step 2: Preparation of3-(4-methyl-3-thioxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

To a stirred suspension of(5R)-3-(3,4-dihydro-4-methyl-3-thioxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylicacid methyl ester (Step 1, 100 mg, 0.2955 mmol) in MeOH (3 mL) is added2.0 M ammonia in MeOH (1.0 mL). This mixture is heated at 40° C. for 24h at which time the reaction is concentrated under reduced pressure. Theresidue is washed with MeOH (4 mL) and purified by column chromatography(2% MeOH/CH₂Cl₂) to give the title compound as a white solid (25 mg,26%), ¹H NMR (300 MHz, DMSO) δ 7.87 (br s, 1H), 7.64 (d, 2H), 7.51 (s,2H), 5.03 (dd, 1H), 4.28 (t, 1H), 4.02 (dd, 1H), 3.85 (s, 2H), 3.32 (s,3H); MS for C₁₃H₁₃N₃O₃S₂ m/z 324.5 (M+H)⁺.

Example 85(5R)-N-Methyl-3-[3-fluoro-4-(trans-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide

Following the general procedure of EXAMPLE 42, and making non-criticalvariations but substitutingbutyl(5R)-3-[3-fluoro-4-(trans-tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 24, Step 1) forbutyl(5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylateand purifying the residue by chromatography on a Biotage Flash 40S 40 gsilica gel cartridge, eluting with a gradient of MeOH/CH₂Cl₂(2/98-4/96), the title compound [R_(f)=0.48 by TLC (MeOH/CHCl₃, 10/90)]is obtained, ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (m, 1H), 7.47 (dd, 1H),7.33 (m, 2H), 5.06 (dd, 1H), 4.27 (t, 1H), 4.00 (dd, 1H), 3.38 (m, 2H),3.06 (m, 1H), 2.81 (m, 2H), 1.99 (m, 2H), 1.88 (m, 2H); MS (ESI+) forC₁₆H₁₉N₂O₄FS m/z 355 (M+H)⁺.

Example 86(5R)-3-(4-Fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 2-(benzyloxy)-6-fluorobenzamide

Benzyl alcohol (24 ml, 0.229 mol) is added portionwise to a suspensionof sodium hydride (9.16 g, 0.229 mol) in DMF (300 ml) and stirred atroom temperature for 1 h. 2,6-Difluorobenzamide (30 g, 0.190 mol) isadded in one portion and stirring is continued overnight at roomtemperature. The reaction mixture is poured into 1N HCl (1.5 l) andextracted with dichloromethane. The extract is washed with water andsaline, dried (MgSO₄), and evaporated to give product as a white solidsuitable for use in the next step (39.6 g, 85%); MS for C₁₄H₁₂FNO₂ m/z246 (M+H)⁺.

Step 2: Preparation of 2-(benzyloxy)-6-fluoroaniline

Sodium hypochlorite (10% aqueous solution, 69.1 ml, 0.112 mol) is addedat 0° C. in portions to a mixture of 2-(benzyloxy)-6-fluorobenzamide(Step 1, 22.89 g, 0.0933 mol) and sodium hydroxide (9.33 g, 0.233 mol)dissolved in water (200 ml) and dioxane (200 ml). The mixture is heatedat 70° C. for 1 h, cooled to room temperature, and then extracted withether. The ether extract is washed with water and saline, dried (MgSO₄),and evaporated to give a light brown oil. Purification by flash columnchromatography (10% ethyl acetate/hexane) gives pure product as acolorless oil (18.2 g, 90%).

Step 3: Preparation of 2-amino-3-fluorophenol

2-(Benzyloxy)-6-fluoroaniline (Step 2, 5.00 g, 0.0230 mol) and 10%palladium on carbon (0.5 g) in methanol (100 ml) are stirred under ahydrogen atmosphere (balloon) for 2 h. The catalyst is removed byfiltration through a pad of celite and the filtrate concentrated to givepure product as a tan solid (2.9 g, 99%); mp 125-6° C.

Step 4: Preparation of 4-fluoro-1,3-benzoxazol-2(3H)-one

1,1′-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to asolution of 2-amino-3-fluorophenol (Step 3, 8.94 g, 0.0703 mol) in THF(200 ml) and warmed at 60° C. for 2 h. The reaction mixture is dilutedwith ethyl acetate (200 ml), washed with 2N HCl and saline, dried(MgSO₄), and evaporated to give product as a white solid suitable foruse in the next step (10.6 g, 99%); mp 131-3° C.

Step 5: Preparation of 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one

Nitric acid (70%, 2.50 ml, 0.0389 mol) is added dropwise at −10° C. to asolution of 4-fluoro-1,3-benzoxazol-2(3H)-one (Step 4, 5.95 g, 0.0389mol) in concentrated sulfuric acid (60 ml). The reaction is stirred at−10° C. for 30 minutes and then poured into ice water. The resultingprecipitate is collected by filtration and dried under reduced pressureto give desired product contaminated with approximately 10-15% of theundesired 5-nitro isomer (7.2 g, 93%); mp 177-9° C.

Step 6: Preparation of4-fluoro-3-methyl-6-nitro-1,3-benzoxazol-2(3H)-one

Iodomethane (0.393 ml, 6.31 mmol) is added in portions to crude4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (Step 5, 1.00 g, 5.05 mmol)and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.94 ml, 6.31 mmol) in DMF (10ml). The reaction is stirred at 65° C. overnight, diluted with ethylacetate, washed with 2N HCl and saline, dried (MgSO₄), and evaporated togive crude product containing trace amounts of undesired 5-nitro isomer.Purification by flash column chromatography (20% ethyl acetate/hexane)gives pure product as a white solid (0.89 g, 83%); mp 118-9° C.

Step 7: Preparation of6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one

Iron powder (0.77 g, 0.0138 mol) is added in small portions to a mixtureof 4-fluoro-3-methyl-6-nitro-1,3-benzoxazol-2(3H)-one (Step 6, 0.73 g,3.44 mmol) and ammonium chloride (1.84 g, 3.44 mmol) in ethanol (30 ml)and water (15 ml) at 95° C. The reaction mixture is stirred vigorouslyand heated for 1 h, cooled to room temperature, and diluted withdichloromethane (150 ml). The mixture is filtered, washed with water andsaline, dried (MgSO₄) and evaporated to give product as a tan solidsuitable for use in the next step (0.64 g, 99%).

Step 8: Preparation of methyl(2R)-3-[(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate

A mixture of 6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (Step 7,0.630 g, 3.46 mmol), methyl (2R)-glycidate (0.353 g, 3.46 mmol) andlithium trifluoromethanesulfonate (0.540 g, 3.46 mmol) in acetonitrile(10 ml) is stirred and heated at 90° C. overnight. The reaction mixtureis diluted with ethyl actetate, washed with water and saline, dried(MgSO₄), and evaporated under reduced pressure. Final purification byflash column chromatography (50% ethyl acetate/hexane) gives pureproduct as a white solid (0.98 g, 60%); MS for C₁₂H₁₃FN₂O₅ m/z 285(M+H)⁺.

Step 9: Preparation ofmethyl(5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate

A mixture of methyl(2R)-3-[(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate(Step 8, 0.84 g, 2.96 mmol) and 1,1′-carbonyldiimidazole (0.48 g, 2.96mmol) in acetonitrile is stirred and heated at 60° C. overnight. Thereaction is diluted with ethyl acetate, washed with 2N HCl and saline,and evaporated under reduced pressure. The resulting solid is trituratedwith methanol to give pure product as a white solid (0.88 g, 96%); MSfor C₁₃H₁₁FN₂O₆ m/z 311 (M+H)⁺.

Step 10: Preparation of(5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

A solution of ammonia in methanol (2M, 5 ml) is added to solidmethyl(5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-1,3-oxazolidine-5-carboxylate(Step 9, 0.250 g, 0.806 mmol) and the suspension stirred overnight atroom temperature. The reaction mixture is concentrated under reducedpressure and the residue purified by PTLC (10% methanol/dichloromethane)to give product as a white solid (0.13 g, 55%); MS for C₁₂H₁₀FN₃O₅ m/z296 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s,1H), 7.50 (d, 1H), 7.42 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.01 (dd,1H), 3.42 (s, 3H).

Example 87 (5R)-3-(3-Ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of 3-ethyl-4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one

Prepared from iodoethane (0.61 ml, 7.57 mmol),4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g,6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol)in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (1.10 g,80%); mp 121-2° C.

Step 2: Preparation of 6-amino-3-ethyl-4-fluoro-1,3-benzoxazol-2(3H)-one

Prepared from 3-ethyl-4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (Step 1,1.05 g, 4.90 mmol), ammonium chloride (2.62 g, 49 mmol) and iron powder(1.09 g, 19.6 mmol) in ethanol (30 ml) and water (15 ml) according tothe method of EXAMPLE 86, Step 7 (0.95 g, 99%).

Step 3: Preparation of methyl(2R)-3-[(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate

Prepared from 6-amino-3-ethyl-4-fluoro-1,3-benzoxazol-2(3H)-one (Step 2,0.90 g, 4.59 mmol), methyl (2R)-glycidate (0.469 g, 4.59 mmol) andlithium trifluoromethanesulfonate (0.716 g, 4.59 mmol) in acetonitrile(10 ml) according to the method of EXAMPLE 86, Step 8 (1.11 g, 81%); MSfor C₁₃H₁₅FN₂O₅ m/z 299 (M+H)⁺.

Step 4: Preparation ofmethyl(5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate

Prepared from methyl(2R)-3-[(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate(Step 3, 1.01 g, 3.39 mmol) and 1,1′-carbonyldiimidazole (0.549 g, 3.39mmol) according to the method of EXAMPLE 86, Step 9 (1.10 g, 99%); MSfor C₁₄H₁₃FN₂O₆ m/z 325 (M+H)⁺.

Step 5: Preparation of(5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Prepared frommethyl(5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(Step 4, 0.250 g, 0.771 mmol) and ammonia in methanol (5 ml) accordingto the method of EXAMPLE 86, Step 10 (0.15 g, 63%); MS for C₁₃H₁₂FN₃O₅m/z 310 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s,1H), 7.52 (d, 1H), 7.44 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.02 (dd,1H), 3.86 (q, 2H), 1.28 (t, 3H).

Example 88(5R)-3-(4-Fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Step 1: Preparation of4-fluoro-3-isopropyl-6-nitro-1,3-benzoxazol-2(3H)-one

Prepared from 2-iodopropane (0.76 ml, 7.57 mmol),4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g,6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol)in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (0.87 g,60%); mp 122-3° C.

Step 2: Preparation of6-amino-4-fluoro-3-isopropyl-1,3-benzoxazol-2(3H)-one

Prepared from 4-fluoro-3-isopropyl-6-nitro-1,3-benzoxazol-2(3H)-one(Step 1, 0.87 g, 3.64 mmol), ammonium chloride (1.95 g, 36.4 mmol) andiron powder (0.81 g, 14.6 mmol) in ethanol (30 ml) and water (15 ml)according to the method of EXAMPLE 86, Step 7 (0.77 g, 99%).

Step 3: Preparation of methyl(2R)-3-[(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate

Prepared from 6-amino-4-fluoro-3-isopropyl-1,3-benzoxazol-2(3H)-one(Step 2, 0.77 g, 3.66 mmol), methyl (2R)-glycidate (0.374 g, 3.66 mmol)and lithium trifluoromethanesulfonate (0.57 g, 3.66 mmol) inacetonitrile (10 ml) according to the method of EXAMPLE 86, Step 8 (0.89g, 78%); MS for C₁₄H₁₇FN₂O₅ m/z 313 (M+H)⁺.

Step 4: Preparation ofmethyl(5R)-3-(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate

Prepared from methyl(2R)-3-[(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate(Step 3, 0.908 g, 2.91 mmol) and 1,1′-carbonyldiimidazole (0.471 g, 2.91mmol) according to the method of EXAMPLE 86, Step 9 (0.90 g, 92%); MSfor C₁₅H₁₅FN₂O₆ m/z 339 (M+H)⁺.

Step 5: Preparation of(5R)-3-(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxamide

Prepared frommethyl(5R)-3-(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(Step 4, 0.250 g, 7.39 mmol) and ammonia in methanol (5 ml) according tothe method of EXAMPLE 86, Step 10 (0.14 g, 59%); MS for C₁₄H₁₄FN₃O₅ m/z324 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 Mhz) δ 7.88 (br s, 1H), 7.63 (br s,1H), 7.53 (d, 1H), 7.44 (dd, 1H), 5.04 (dd, 1H), 4.55 (m, 1H), 4.26 (t,1H), 4.02 (dd, 1H), 1.41 (dd, 6H).

Example 89(5R)-3-(4-Fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-N-methyl-2-oxo-5-oxazolidinecarboxamide

A solution of methylamine in methanol (2M, 5 ml) is added to solidmethyl(5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 86, Step 9, 0.250 g, 0.806 mmol) and the suspension stirredovernight at room temperature. The reaction mixture is concentratedunder reduced pressure and the residue purified by PTLC (10%methanol/dichloromethane) to give product as a white solid (0.049 g,19%); MS for C₁₃H₁₂FN₃O₅ m/z 310 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 Mhz) δ8.40 (m, 1H), 7.49 (d, 1H), 7.42 (dd, 1H), 5.07 (dd, 1H), 4.26 (t, 1H),4.02 (dd, 1H), 3.42 (s, 3H), 2.65 (d, 3H).

Example 90(5R)-3-(3-Ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-N-methyl-2-oxo-5-oxazolidinecarboxamide

A solution of methylamine in methanol (2M, 5 ml) is added to solidmethyl(5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 87, Step 4, 0.250 g, 0.771 mmol) and the suspension stirredovernight at room temperature. The reaction mixture is concentratedunder reduced pressure and the residue purified by PTLC (10%methanol/dichloromethane) to give product as a white solid (0.10 g,40%); MS for C₁₄H₁₄FN₃O₅ m/z 324 (+H)⁺; ¹H NMR (DMSO-d₆, 300 Mhz) δ 8.40(m, 1H), 7.51 (d, 1H), 7.44 (dd, 1H), 5.07 (dd, 1H), 4.27 (t, 1H), 4.02(dd, 1H), 3.85 (q, 2H), 2.65 (d, 3H), 1.28 (t, 3H).

Example 91(5R)-3-(4-Fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-N-methyl-2-oxo-5-oxazolidinecarboxamide

A solution of methylamine in methanol (2M, 5 ml) is added to solidmethyl(5R)-3-(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate(EXAMPLE 88, Step 4, 0.250 g, 0.739 mmol) and the suspension stirredovernight at room temperature. The reaction mixture is concentratedunder reduced pressure and the residue purified by PTLC (10%methanol/dichloromethane) to give product as a white solid (0.05 g,20%); MS for C₁₅H₁₆FN₃O₅ m/z 338 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 Mhz) δ8.40 (m, 1H), 7.52 (d, 1H), 7.43 (dd, 1H), 5.08 (dd, 1H), 4.54 (m, 1H),4.27 (t, 1H), 4.03 (dd, 1H), 2.65 (d, 3H), 1.41 (dd, 6H).

Example 92

Other compounds of this invention may be synthesized via the methodologydescribed herein. For instance, FIGS. I-V provide exemplary proceduresfor producing pyridine/pyrimidine-phenyl oxazolidinonecarboxamides(Compounds 48-91 below); FIGS. VI-IX provide exemplary procedures forproducing tetrahydropyridyl/thiopyranyl/pyranyl-phenyloxazolidinonecarboxamides (Compounds 92-137 below); FIGS. X-XV provideexemplary procedures for producing benzooxazolyl/benzthiazolyl-phenyloxazolidinonecarboxamides (Compounds 138-171 below); FIGS. XVI-XVIIprovide exemplary procedures for producingfluorenyl/phenanthrenyl/pyrido[1,2-a]quinolinyl-phenyloxazolidinonecarboxamides (Compounds 172-223 below); FIG. XVIII providesan exemplary procedure for producing bicyclo[3.1.0]hexyl-phenyloxazolidinonecarboxamides (Compounds 224-231 below); FIGS. XIX-XXVIprovide exemplary procedures for producing benzo[e]azulenyl-phenyloxazolidinonecarboxamides (Compounds 232-301 below); FIGS. XXVII-XXVIIIprovide exemplary procedures for producingoxo-benzooxazolyl/oxo-benzothiazolyl-phenyl oxazolidinonecarboxamides(Compounds 302-321 below); and FIGS. XXIX-XXIX provide exemplaryprocedures for producing benzooxazinyl/benzothiazinyl-phenyloxazolidinonecarboxamides (Compounds 322-337 below).

Additional compounds of the invention include, but are not limited to,the following:

-   1.    (5R)-3-(2-Formyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   2.    (5R)-N-Methyl-3-(2-formyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-2-oxo    -5-oxazolidinecarboxamide-   3.    (5R)-3-[2-(Hydroxyacetyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl]-2-oxo    -5-oxazolidinecarboxamide-   4.    (5R)-N-Methyl-3-[2-(hydroxyacetyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl]-2-oxo-5-oxazolidinecarboxamide-   5.    (5R)-3-(3-Formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   6.    (5R)-N-Methyl-3-(3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-oxo    -5-oxazolidinecarboxamide-   7.    (5R)-3-[3-(Hydroxyacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-5-oxazolidinecarboxamide-   8.    (5R)-N-Methyl-3-[3-(hydroxyacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-oxo-5-oxazolidinecarboxamide-   9.    (5R)-3-[3,5-Difluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   10.    (5R)-N-Methyl-3-[3,5-difluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   11.    (5R)-3-[3-Fluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   12.    (5R)-N-Methyl-3-[3-fluoro-4-(1-formyl-3-methylazetidin-3-yl)phenyl]-2-oxo    -5-oxazolidinecarboxamide-   13.    (5R)-3-[4-(cis-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran    -4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   14.    (5R)-N-Methyl-3-[4-(cis-1-imino-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran    -4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   15.    (5R)-N-Methyl-3-[4-(cis-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran    -4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   16.    (5R)-3-[4-(trans-1-(imino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   17.    (5R)-N-Methyl-3-[4-(trans-1-(imino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran    -4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   18.    (5R)-3-[4-(trans-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro-2H-thiopyran    -4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   19.    (5R)-N-Methyl-3-[4-(trans-1-(methylimino)-1-oxido-1,1,3,4,5,6-hexahydro    -2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   20.    (5R)-3-[4-(1-(2(S)-Hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid    -4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   21.    (5R)-N-Methyl-3-[4-(1-(2(S)-hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   22.    (5R)-3-[4-(1-(2(S),3-Dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   23.    (5R)-N-Methyl-3-[4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   24.    (5R)-3-[4-(1-(2(S)-Hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   25.    (5R)-N-Methyl-3-[4-(1-(2(S)-hydroxy-3-phosphorylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   26.    (5R)-3-[4-(1-(2(S),3-Dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide;    and-   27.    (5R)-N-Methyl-3-[4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide-   28.    (5R)-3-(3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   29.    (5R)-N-Methyl-3-(3,4-dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   30.    (5R)-3-(3,4-Dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   31.    (5R)-N-Methyl-3-(3,4-dihydro-5-fluoro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   32.    (5R)-3-(2,3-Dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide-   33.    (5R)-N-Methyl-3-(2,3-dihydro-3-methyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide-   34.    (5R)-3-(2,3-Dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide-   35.    (5R)-N-Methyl-3-(2,3-dihydro-3-ethyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide-   36.    (5R)-3-(2,3-Dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide-   37.    (5R)-N-Methyl-3-(2,3-dihydro-3-isopropyl-4-fluoro-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxamide-   38.    (5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide-   39.    (5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-N-methyl-2-oxo-5-oxazolidinecarboxamide    S,S-dioxide-   40.    (5R)-3-[3-Fluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   41.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   42.    (5R)-3-[3-Fluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   43.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   44.    (5R)-3-[3,5-Difluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   45.    (5R)-N-Methyl-3-[3,5-Difluoro-4-(1-imino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   46.    (5R)-3-[3,5-Difluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   47.    (5R)-N-Methyl-3-[3,5-Difluoro-4-(1-methylimino-1-oxido-4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxamide-   48.    (5R)-3-{3-Fluoro-4-[6-(1-methyl-1H-tetrazol-5-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   49.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(1-methyl-1H-tetrazol-5-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   50.    (5R)-N-Methyl-3-[3-Fluoro-4-(6-[1,2,4]triazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   51.    (5R)-3-[3-Fluoro-4-(6-[1,2,4]triazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   52.    (5R)-3-{3-Fluoro-4-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   53.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   54.    (5R)-N-Methyl-3-[3-Fluoro-4-(6-tetrazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   55.    (5R)-3-[3-Fluoro-4-(6-tetrazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   56.    (5R)-3-[3-Fluoro-4-(6-pyrazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   57.    (5R)-N-Methyl-3-[3-Fluoro-4-(6-pyrazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   58.    (5R)-3-[3-Fluoro-4-(6-[1,2,3]triazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   59.    (5R)-3-[3-Fluoro-4-(6-[1,2,3]triazol-1-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   60.    (5R)-3-{3-Fluoro-4-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   61.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   62.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(2-oxo-oxazolidin-3-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   63.    (5R)-3-{3-Fluoro-4-[6-(2-oxo-oxazolidin-3-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   64.    (5R)-3-{3-Fluoro-4-[6-(2-oxo-imidazolidin-1-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   65.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(2-oxo-imidazolidin-1-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   66.    (5R)-3-[3-Fluoro-4-(6-oxazol-5-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   67.    (5R)-N-Methyl-3-[3-Fluoro-4-(6-oxazol-5-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   68.    (5R)-N-Methyl-3-[3-Fluoro-4-(6-[1,2,4]oxadiazol-3-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   69.    (5R)-3-[3-Fluoro-4-(6-[1,2,4]oxadiazol-3-yl-pyridin-3-yl)-phenyl]-2-oxo-5-oxazolidinecarboxylicamide-   70.    (5R)-3-{3-Fluoro-4-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   71.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   72.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   73.    (5R)-3-{3-Fluoro-4-[6-(5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   74.    (5R)-3-[4-(6-Acetylamino-pyridin-3-yl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   75.    (5R)-3-[4-(6-Acetylamino-pyridin-3-yl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   76.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(2-hydroxy-acetylamino)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   77.    (5R)-3-{3-Fluoro-4-[6-(2-hydroxy-acetylamino)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   78.    (5R)-3-{3-Fluoro-4-[6-(4-hydroxyacetyl-piperazin-1-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   79.    (5R)-N-Methyl-3-{3-Fluoro-4-[6-(4-hydroxyacetyl-piperazin-1-yl)-pyridin-3-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   80.    (5R)-N-Methyl-3-{3-Fluoro-4-[2-(4-hydroxyacetyl-piperazin-1-yl)-pyrimidin-5-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   81.    (5R)-N-Methyl-3-{3-Fluoro-4-[2-(4-hydroxyacetyl-piperazin-1-yl)-pyrimidin-5-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   82.    (5R)-3-{4-[6-(4-Cyano-piperazin-1-yl)-pyridin-3-yl]-3-fluoro-phenyl}-2-oxo-5-oxazolidinecarboxamide-   83.    (5R)-N-Methyl-3-{4-[6-(4-Cyano-piperazin-1-yl)-pyridin-3-yl]-3-fluoro-phenyl}-2-oxo-5-oxazolidinecarboxamide-   84.    (5R)-N-Methyl-3-{4-[2-(4-Cyano-piperazin-1-yl)-pyrimidin-5-yl]-3-fluoro-phenyl}-2-oxo-5-oxazolidinecarboxamide-   85.    (5R)-N-Methyl-3-{4-[2-(4-Cyano-piperazin-1-yl)-pyrimidin-5-yl]-3-fluoro-phenyl}-2-oxo-5-oxazolidinecarboxamide-   86.    (5R)-3-[3-Fluoro-4-(4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   87.    (5R)-N-Methyl-3-[3-Fluoro-4-(4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   88.    (5R)-N-Methyl-3-[3-Fluoro-4-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   89.    (5R)-3-[3-Fluoro-4-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   90.    (5R)-N-Methyl-3-[3-Fluoro-4-(4-hydroxyimino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   91.    (5R)-3-[3-Fluoro-4-(4-hydroxyimino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   92.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-hydroxyacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-oxazolidine-5-carboxamide-   93.    (5R)-3-[3-Fluoro-4-(1-hydroxyacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-oxazolidine-5-carboxamide-   94.    (5R)-3-{4-[1-((2S),3-Dihydroxy-propionyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenyl}-2-oxo-5-oxazolidinecarboxamide-   95.    (5R)-N-Methyl-3-{4-[1-((2S),3-Dihydroxy-propionyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenyl}-2-oxo-5-oxazolidinecarboxamide-   96.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-methoxyacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   97.    (5R)-3-[3-Fluoro-4-(1-methoxyacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   98.    (5R)-3-[3-Fluoro-4-(1-methylsulfanylacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   99.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-methylsulfanylacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidine    carboxamide-   100.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-formyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   101.    (5R)-3-[3-Fluoro-4-(1-formyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   102.    (5R)-N-Methyl-4-[4-(5-Carbamoyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic    acid methylamide

-   103.    4-[4-(5-Carbamoyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic    acid amide

-   104.    4-[4-(5-Carbamoyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic    acid amide

-   105.    4-[4-(5-Carbamoyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic    acid methylamide

-   106. 4-[4-(5-Carbamoyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-3,6

-    dihydro-2H-pyridine-1-carboxylic acid methyl ester-   107.    4-[2-Fluoro-4-(5-methylcarbamoyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic    acid methyl ester

-   108.    (5R)-N-Methyl-3-[4-(1-Cyano-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   109.    (5R)-3-[4-(1-Cyano-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   110.    (5R)-3-[3-Fluoro-4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   111.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin    -4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   112.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin    -4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   113.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin    -4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   114.    (5R)-3-{3-Fluoro-4-[1-(3-oxo-butyryl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   115.    (5R)-N-Methyl-3-{3-Fluoro-4-[1-(3-oxo-butyryl)-1,2,3,6-tetrahydro-pyridin    -4-yl]-phenyl}-2-oxo-5-oxazolidinecarboxamide-   116.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-methanesulfonylaminoacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   117.    (5R)-3-[3-Fluoro-4-(1-methanesulfonylaminoacetyl-1,2,3,6-tetrahydro-pyridin    -4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   118.    (5R)-3-[3-Fluoro-4-(1-oxo-1,2,3,6-tetrahydro-1λ⁴-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   119.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-oxo-1,2,3,6-tetrahydro-1λ⁴-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   120.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-imino-1-oxo-1,2,3,6-tetrahydro-1-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   121.    (5R)-3-[3-Fluoro-4-(1-imino-1-oxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   122.    (5R)-3-[3-Fluoro-4-(1-methylimino-1-oxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   123.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-methylimino-1-oxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   124.    (5R)-N-Methyl-3-[4-(1-Acetylimino-1-oxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   125.    (5R)-3-[4-(1-Acetylimino-1-oxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   126.    (5R)-3-[3-Fluoro-4-(1-hydroxyacetylimino-1-oxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   127.    (5R)-N-Methyl-3-[3-Fluoro-4-(1-hydroxyacetylimino-1-oxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   128.    (5R)-N-Methyl-3-[4-(1,1-Dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-3,5-difluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   129.    (5R)-3-[4-(1,1-Dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-3,5-difluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   130.    (5R)-3-[4-(1,1-Dioxo-1,2-dihydro-1λ⁶-thiopyran-4-yl)-3,5-difluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   131.    (5R)-N-Methyl-3-[4-(1,1-Dioxo-1,2-dihydro-1λ⁶-thiopyran-4-yl)-3,5-difluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   132.    3-[4-(1,2-dihydro-pyran-4-yl)-3,5-difluoro-phenyl]-2-oxo-oxazolidine-5-carboxylic    acid methylamide-   133.    3-[4-(1,1-Dioxo-1,2-dihydro-1λ⁶-thiopyran-4-yl)-3,5-difluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   134.    (5R)-3-[3,5-Difluoro-4-(tetrahydro-pyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   135.    (5R)-N-Methyl-3-[3,5-Difluoro-4-(tetrahydro-pyran-4-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   136.    (5R)-N-Methyl-3-[3,5-Difluoro-4-(4-oxo-cyclohex-1-enyl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   137.    (5R)-3-[3,5-Difluoro-4-(4-oxo-cyclohex-1-enyl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   138.    (5R)-3-(4-Fluoro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   139.    (5R)-N-Methyl-3-(4-Fluoro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   140.    (5R)-N-Methyl-3-(4-Fluoro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   141.    (5R)-3-(4-Fluoro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   142.    (5R)-3-(4-Fluoro-2-methyl-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   143.    (5R)-N-Methyl-3-(4-Fluoro-2-methyl-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   144.    (5R)-N-Methyl-3-(4-Fluoro-2-methanesulfinyl-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   145.    (5R)-3-(4-Fluoro-2-methanesulfinyl-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   146.    (5R)-3-(4-Fluoro-2-methanesulfinyl-benzoxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   147.    (5R)-N-Methyl-3-(4-Fluoro-2-methanesulfinyl-benzoxazol-6-yl)-2-oxo    -5-oxazolidinecarboxamide-   148.    (5R)-N-Methyl-3-(4-Fluoro-2-methanesulfonyl-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   149.    (5R)-3-(4-Fluoro-2-methanesulfonyl-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   150.    (5R)-N-Methyl-3-(4-Fluoro-2-methanesulfonyl-benzothiazol-6-yl)-2-oxo    -5-oxazolidinecarboxamide-   151.    (5R)-3-(4-Fluoro-2-methanesulfonyl-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   152.    (5R)-3-(4-Fluoro-2-morpholin-4-yl-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   153.    (5R)-3-(4-Fluoro-2-morpholin-4-yl-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   154.    (5R)-N-Methyl-3-(4-Fluoro-2-thiomorpholin-4-yl-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   155.    (5R)-3-(4-Fluoro-2-thiomorpholin-4-yl-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   156.    (5R)-3-[2-(1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)-4-fluoro-benzothiazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   157.    (5R)-N-Methyl-3-[2-(1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)-4-fluoro-benzothiazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   158.    (5R)-N-Methyl-3-[4-Fluoro-2-(4-oxo-piperidin-1-yl)-benzothiazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   159.    (5R)-3-[4-Fluoro-2-(4-oxo-piperidin-1-yl)-benzothiazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   160.    (5R)-3-[4-Fluoro-2-(4-oxo-piperidin-1-yl)-benzoxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   161.    (5R)-N-Methyl-3-[4-Fluoro-2-(4-oxo-piperidin-1-yl)-benzoxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   162.    (5R)-N-Methyl-3-[4-Fluoro-2-(4-oxo-4H-pyridin-1-yl)-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   163.    (5R)-3-[4-Fluoro-2-(4-oxo-4H-pyridin-1-yl)-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   164.    (5R)-3-[4-Fluoro-2-(4-oxo-4H-pyridin-1-yl)-benzothiazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   165.    (5R)-N-Methyl-3-[4-Fluoro-2-(4-oxo-4H-pyridin-1-yl)-benzothiazol-6-yl]-2-oxo-5-oxazolidine-5-carboxamide-   166.    (5R)-N-Methyl-3-(2-Amino-4-fluoro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   167.    (5R)-3-(2-Amino-4-fluoro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   168.    (5R)-3-(2-Amino-4-fluoro-benzoxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   169.    (5R)-N-Methyl-3-(2-Amino-4-fluoro-benzoxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   170.    (5R)-N-Methyl-3-[4-Fluoro-2-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-benzooxazol    -6-yl]-2-oxo-5-oxazolidinecarboxamide-   171.    (5R)-3-[2-(4-oxo-3,4-dihydro-2-H-pyridin-1-yl)-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   172.    (5R)-N-Methyl-3-(4,4-Difluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   173.    (5R)-3-(4,4-Difluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   174.    (5R)-3-(4,4,8-trifluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   175.    (5R)-N-Methyl-3-(4,4,8-trifluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   176.    (5R)-N-Methyl-3-(5-Fluoro-2-oxo-3,4-dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide-   177.    (5R)-3-(5-Fluoro-2-oxo-3,4-dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide-   178.    (5R)-3-(2-oxo-3,4-dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide-   179.    (5R)-N-Methyl-3-(2-oxo-3,4-dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)    -2-oxo-5-oxazolidinecarboxamide-   180.    (5R)-N-Methyl-3-(2-oxo-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   181.    (5R)-3-(2-oxo-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   182.    (5R)-N-Methyl-3-(5-Fluoro-2-oxo-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   183.    (5R)-3-(5-Fluoro-2-oxo-3,4-dihydro-2H-9-thia-1,4a-diaza-fluoren-7-yl)    -2-oxo-5-oxazolidinecarboxamide-   184.    (5R)-N-Methyl-3-(2-oxo-3,4-dihydro-2H-9-thia-1,4a-diaza-fluoren-7-yl)    -2-oxo-5-oxazolidinecarboxamide

-   185.    (5R)-3-(2-oxo-3,4-dihydro-2H-9-thia-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   186.    (5R)-3-(2-oxo-2H-9-thia-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   187.    (5R)-3-(3,4-Dihydro-2H-9-thia-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide-   188.    3-(3,4-Dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   189.    (5R)-3-(5-Fluoro-3,4-dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   190.    (5R)-N-methyl-3-(5-Fluoro-3,4-dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   191.    (5R)-N-methyl-3-(5-Fluoro-3,4-dihydro-2-H-9-thia-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   192.    (5R)-3-(5-Fluoro-3,4-dihydro-2-H-9-thia-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   193.    (5R)-3-(5-Fluoro-2-hydroxy-3,4-dihydro-2H-9-thia-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   194.    (5R)-3-(5-Fluoro-2-hydroxy-3,4-dihydro-2H-9-oxa-1,4a-diaza-fluoren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   195.    (5R)-3-(5-Fluoro-2-oxo-2,3,4,10-tetrahydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   196.    (5R)-N-methyl-3-(5-Fluoro-2-oxo-2,3,4,10-tetrahydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   197.    (5R)-N-methyl-3-(5-Fluoro-2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   198.    (5R)-3-(5-Fluoro-2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   199.    (5R)-3-(2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren-7-yl)-5-oxazolidinecarboxamide

-   200.    (5R)-3-(2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   201.    (5R)-N-methyl-3-(10,10-Difluoro-2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren    -7-yl)-2-oxo-5-oxazolidinecarboxamide

-   202.    (5R)-3-(10,10-Difluoro-2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   203.    (5R)-3-(5,10,10-trifluoro-2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren    -7-yl)-2-2oxo-5-oxazolidinecarboxamide

-   204.    (5R)-3-(5,10,10-trifluoro-2-oxo-2,10-dihydro-9-oxa-4a-aza-phenanthren    -7-yl)-2-oxo-5-oxazolidinecarboxamide

-   205.    (5R)-3-(5,10,10-trifluoro-2-oxo-2,3,4,10-tetrahydro-9-oxa-4a-aza-phenanthren    -7-yl)-2-oxo-5-oxazolidinecarboxamide

-   206.    (5R)-3-(5,10,10-trifluoro-2-oxo-2,3,4,10-tetrahydro-9-oxa-4a-aza-phenanthren    -7-yl)-2-oxo-5-oxazolidinecarboxamide

-   207.    (5R)-3-(5-Fluoro-2-oxo-1,2,10,10a-tetrahydro-9-oxa-4a-aza-phenanthren    -7-yl)-2-oxo-5-oxazolidinecarboxamide

-   208.    (5R)-3-(5-Fluoro-2-oxo-1,2,10,10a-tetrahydro-9-oxa-4a-aza-phenanthren    -7-yl)-2-oxo-5-oxazolidinecarboxamide

-   209.    (5R)-N-methyl-3-(2-oxo-1,2,10,10a-tetrahydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   210.    (5R)-3-(2-oxo-1,2,10,10a-tetrahydro-9-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   211.    (5R)-3-(3-oxo-2,3,5,6-tetrahydro-1H-pyrido[1,2-α]quinolin-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   212.    (5R)-N-methyl-3-(3-oxo-2,3,5,6-tetrahydro-1H-pyrido[1,2-α]quinolin-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   213.    (5R)-N-methyl-3-(3-oxo-5,6-dihydro-3H-pyrido[1,2-α]quinolin-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   214.    (5R)-N-methyl-2-Oxo-3-(3-oxo-5,6-dihydro-3H-pyrido[1,2-α]quinolin-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   215.    (5R)-3-(10-Fluoro-3-oxo-5,6-dihydro-3H-pyrido[1,2-α]quinolin-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   216.    (5R)-3-(10-Fluoro-3-oxo-5,6-dihydro-3H-pyrido[1,2-α]quinolin-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   217.    (5R)-N-methyl-3-(10-Fluoro-3-oxo-4,4a,5,6-tetrahydro-3H-pyrido[1,2-α]quinolin-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   218.    (5R)-N-methyl-3-(5-Fluoro-2-oxo-2H,9H-10-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   219.    (5R)-3-(5-Fluoro-2-oxo-2H,9H-10-oxa-4a-aza-phenanthren-7-yl)-2-oxo    -5-oxazolidinecarboxamide

-   220.    (5R)-3-(5-Fluoro-2-oxo-3,4-dihydro-2H,9H-10-oxa-4a-aza-phenanthren    -7-yl)-2-oxo-5-oxazolidinecarboxamide

-   221.    (5R)-N-methyl-3-(5-Fluoro-2-oxo-3,4-dihydro-2H,9H-10-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   222.    (5R)-N-methyl-3-(2-oxo-3,4-dihydro-2-H,9H-10-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   223.    (5R)-3-(2-oxo-3,4-dihydro-2H,9H-10-oxa-4a-aza-phenanthren-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   224.    (5R)-3-[3-Fluoro-4-(3-oxo-bicyclo[3.1.0]hex-6-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   225.    (5R)-3-[3-Fluoro-4-(3-hydroxy-bicyclo[3.1.0]hex-6-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   226.    (5R)-3-[3-Fluoro-4-(3-hydroxy-3-aza-bicyclo[3.1.0]hex-6-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   227.    (5R)-3-[3-Fluoro-4-(3-methoxy-3-aza-bicyclo[3.1.0]hex-6-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   228.    (5R)-3-[4-(3-Cyano-3-aza-bicyclo[3.1.0]hex-6-yl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   229.    (5R)-3-[3-Fluoro-4-(2-oxo-3-oxa-bicyclo[3.1.0]hex-6-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   230.    (5R)-3-[3-Fluoro-4-(2-oxo-3-aza-bicyclo[3.1.0]hex-6-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   231.    (5R)-3-[3-Fluoro-4-(3-methyl-2-oxo-3-aza-bicyclo[3.1.0]hex-6-yl)-phenyl]-2-oxo-5-oxazolidinecarboxamide

-   232.    (5R)-3-(1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   233.    (5R)-N-methyl-3-(1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   234.    (5R)-N-ethyl-3-(1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   235.    (5R)-3-(5,6-Dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   236.    (5R)-N-methyl-3-(5,6-Dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   237.    (5R)-N-ethyl-3-(5,6-Dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   238.    (5R)-3-(1,4,5,6-tetrahydro-1,2,10-triaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   239.    (5R)-N-methyl-3-(1,4,5,6-tetrahydro-1,2,10-triaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   240.    (5R)-N-ethyl-3-(1,4,5,6-tetrahydro-1,2,10-triaza-benzo[e]azulen-8-yl)-2-oxo    -5-oxazolidinecarboxamide

-   241.    (5R)-3-(5,6-Dihydro-4H-1-oxa-2,10-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   242.    (5R)-N-methyl-3-(5,6-Dihydro-4H-1-oxa-2,10-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   243.    (5R)-N-ethyl-3-(5,6-Dihydro-4H-1-oxa-2,10-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   244.    (5R)-3-(10-Fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   245.    (5R)-N-methyl-3-(10-Fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   246.    (5R)-N-ethyl-3-(10-Fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   247.    (5R)-3-(10-Fluoro-5,6-dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   248.    (5R)-N-methyl-3-(10-Fluoro-5,6-dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   249.    (5R)-N-ethyl-3-(10-Fluoro-5,6-dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)    -2-oxo-5-oxazolidinecarboxamide

-   250.    (5R)-3-(7-Fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   251.    (5R)-N-methyl-3-(7-Fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)    -2-oxo-5-oxazolidinecarboxamide

-   252.    (5R)-N-ethyl-3-(7-Fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)    -2-oxo-5-oxazolidinecarboxamide

-   253.    (5R)-3-(7-Fluoro-5,6-dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   254. (5R)-N-methyl-3-(7-Fluoro-5,6-dihydro-4H-1-oxa-2-aza-benzo    [e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   255.    (5R)-N-ethyl-3-(7-Fluoro-5,6-dihydro-4H-1-oxa-2-aza-benzo[e]azulen-8-yl)    -2-oxo-5-oxazolidinecarboxamide

-   256.    (5R)-3-(4,5-Dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   257.    (5R)-N-Methyl-3-(4,5-Dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   258.    (5R)-N-ethyl-3-(4,5-Dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   259.    (5R)-3-(4,5-Dihydro-1,6-dioxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   260.    (5R)-N-methyl-3-(4,5-Dihydro-1,6-dioxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   261.    (5R)-N-ethyl-3-(4,5-Dihydro-1,6-dioxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   262.    (5R)-3-(3-Isoxazol-5-yl-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   263.    (5R)-N-methyl-3-(3-Isoxazol-5-yl-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   264.    (5R)-N-ethyl-3-(3-Isoxazol-5-yl-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen    -8-yl)-2-oxo-5-oxazolidinecarboxamide

-   265.    (5R)-3-(3-Isoxazol-5-yl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   266.    (5R)-N-methyl-3-(3-Isoxazol-5-yl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-oxazolidine-5-carboxylic    acid methylamide

-   267.    (5R)-N-ethyl-3-(3-Isoxazol-5-yl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   268.    (5R)-3-(7-Fluoro-3-isoxazol-5-yl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   269.    (5R)-3-(7-Fluoro-3-isoxazol-5-yl-4,5-dihydro-1,6-dioxa-2-aza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   270.    (5R)-3-(3-Methylamino-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   271.    (5R)-N-methyl-3-(3-Methylamino-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-oxazolidine-5-carboxylic    acid methylamide

-   272.    (5R)-N-ethyl-3-(3-Methylamino-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen    -8-yl)-2-oxo-5-oxazolidinecarboxamide

-   273.    (5R)-3-(3-Methylamino-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   274.    (5R)-N-methyl-3-(3-Methylamino-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   275.    (5R)-N-ethyl-3-(3-Methylamino-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   276.    (5R)-3-(3-Methoxy-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   277.    (5R)-N-methyl-3-(3-Methoxy-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   278.    (5R)-N-ethyl-3-(3-Methoxy-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen    -8-yl)-2-oxo-5-oxazolidinecarboxamide

-   279.    (5R)-3-(3-Methoxy-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo    -5-oxazolidinecarboxamide

-   280.    (5R)-N-methyl-3-(3-Methoxy-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   281.    (5R)-N-ethyl-3-(3-Methoxy-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   282.    (5R)-3-(3-Ethyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   283.    (5R)-N-methyl-3-(3-Ethyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide-   284.    (5R)-3-(3-Ethyl-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   285.    (5R)-N-methyl-3-(3-Ethyl-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide-   286.    (5R)-N-ethyl-3-(3-Ethyl-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide-   287.    (5R)-3-(3-Ethyl-7-fluoro-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   288.    (5R)-N-methyl-3-(3-Ethyl-10-fluoro-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide-   289.    (5R)-3-(3-Ethyl-10-fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   290.    (5R)-N-methyl-3-(3-Ethyl-10-fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   291.    (5R)-3-(3-Ethyl-7-fluoro-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   292.    (5R)-3-(7-Fluoro-3-methoxy-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   293.    (5R)-N-methyl-3-(10-Fluoro-3-methoxy-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   294.    (5R)-3-(10-Fluoro-3-methoxy-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   295.    (5R)-N-methyl-3-(10-Fluoro-3-methoxy-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   296.    (5R)-3-(7-Fluoro-3-methoxy-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   297.    (5R)-3-(7-Fluoro-3-methylamino-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   298.    (5R)-N-methyl-3-(10-Fluoro-3-methylamino-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   299.    (5R)-3-(10-Fluoro-3-methylamino-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide

-   300.    (5R)-N-methyl-3-(10-Fluoro-3-methylamino-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide-   301.    (5R)-3-(7-Fluoro-3-methylamino-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulen-8-yl)-2-oxo-5-oxazolidinecarboxamide-   302.    (5R)-3-(3-tert-Butyl-4-fluoro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   303.    (5R)-N-methyl-3-(3-tert-Butyl-4-fluoro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   304.    (5R)-3-(3-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   305.    (5R)-N-methyl-3-(3-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   306.    (5R)-3-[4-Fluoro-2-oxo-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   307.    (5R)-N-ethyl-3-(3-tert-Butyl-2-oxo-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   308.    (5R)-N-ethyl-3-[4-Fluoro-2-oxo-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol    -6-yl]-2-oxo-5-oxazolidinecarboxamide-   309.    (5R)-3-(3-tert-Butyl-2-oxo-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   310.    (5R)-N-methyl-3-(3-tert-Butyl-2-oxo-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   311.    (5R)-N-methyl-3-[4-Fluoro-2-oxo-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol    -6-yl]-2-oxo-5-oxazolidinecarboxamide

-   312.    (5R)-3-[2-oxo-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzothiazol-6-yl]-2-oxo    -5-oxazolidinecarboxamide

-   313.    (5R)-N-methyl-3-[2-oxo-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzothiazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   314.    (5R)-3-[2-oxo-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol-6-yl]-2-oxo    -5-oxazolidinecarboxamide

-   315.    (5R)-3-(3-Cyclopropyl-4-fluoro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   316.    (5R)-N-methyl-3-(3-Cyclopropyl-4-fluoro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   317.    (5R)-3-(3-Cyclopropyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   318.    (5R)-N-Methyl-3-(3-Cyclopropyl-2-oxo-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   319.    (5R)-3-(3-Cyclopropyl-4-fluoro-2-oxo-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   320.    (5R)-N-methyl-3-(3-Cyclopropyl-4-fluoro-2-oxo-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   321.    (5R)-3-[3-(2,3-Difluoro-cyclopropyl)-4-fluoro-2-oxo-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   322.    (5R)-3-(4-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   323.    (5R)-N-methyl-3-(4-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   324.    (5R)-3-(4-tert-Butyl-5-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   325.    (5R)-N-methyl-3-(4-tert-Butyl-5-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   326.    (5R)-3-(4-tert-Butyl-5-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   327.    (5R)-3-(4-tert-Butyl-5-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   328.    (5R)-3-(4-Cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   329.    (5R)-N-methyl-3-(4-Cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   330.    (5R)-3-(4-Cyclopropyl-5-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   331.    (5R)-N-methyl-3-(4-Cyclopropyl-5-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   332.    (5R)-3-(4-Cyclopropyl-5-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   333.    (5R)-3-[3-oxo-4-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide

-   334.    (5R)-N-methyl-3-[3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide-   335.    (5R)-3-[5-Fluoro-3-oxo-4-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide

-   336.    (5R)-N-methyl-3-[5-Fluoro-3-oxo-4-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide-   337.    (5R)-3-[5-Fluoro-3-oxo-4-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-benzo[1,4]thiazin-7-yl]-2-oxo-5-oxazolidinecarboxamide

-   338.    (R)-3-(3-tert-Butyl-2-ethylimino-4-fluoro-2,3-dihydro-benzooxazol-6-yl)-2-3    oxo-5-oxazolidinecarboxamide

-   339.    (5R)-N-methyl-3-(3-tert-Butyl-2-ethylimino-4-fluoro-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   340.    (5R)-3-(3-tert-Butyl-2-ethylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   341.    (5R)-N-methyl-3-(3-tert-Butyl-2-ethylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   342.    (5R)-3-[2-Ethylimino-4-fluoro-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   343.    (5R)-3-(3-tert-Butyl-4-fluoro-2-methoxyimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   344.    (5R)-N-methyl-3-(3-tert-Butyl-4-fluoro-2-methoxyimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   345.    (5R)-3-(3-tert-Butyl-2-methoxyimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   346.    (5R)-N-methyl-3-(3-tert-Butyl-2-methoxyimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   347.    (5R)-3-[4-Fluoro-2-methoxyimino-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   348.    (5R)-3-[3-tert-Butyl-4-fluoro-2-(2-hydroxy-ethoxyimino)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   349.    (5R)-N-methyl-3-[3-tert-Butyl-4-fluoro-2-(2-hydroxy-ethoxyimino)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   350.    (5R)-3-[3-tert-Butyl-2-(2-hydroxy-ethoxyimino)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   351.    (5R)-N-methyl-3-[3-tert-Butyl-2-(2-hydroxy-ethoxyimino)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide-   352.    (5R)-3-[4-Fluoro-2-(2-hydroxy-ethoxyimino)-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   353.    (5R)-3-(3-tert-Butyl-2-ethylimino-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide

-   354.    (5R)-N-methyl-3-(3-tert-Butyl-2-ethylimino-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   355.    (5R)-N-methyl-3-[2-Ethylimino-4-fluoro-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   356.    (5R)-3-[3-tert-Butyl-2-(2-hydroxy-ethylimino)-2,3-dihydro-oxazolo[4,5-b]pyridin-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   357.    (5R)-N-methyl-3-[3-tert-Butyl-2-(2-hydroxy-ethylimino)-2,3-dihydro-oxazolo[4,5-b]pyridin-6-yl]-2-oxo-5-oxazolidinecarboxamide-   358.    (5R)-3-[3-tert-Butyl-2-(2-hydroxy-ethylimino)-2,3-dihydro-benzothiazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   359.    (5R)-N-methyl-3-[3-tert-Butyl-2-(2-hydroxy-ethylimino)-2,3-dihydro-benzothiazol    -6-yl]-2-oxo-5-oxazolidinecarboxamide-   360.    (5R)-N-methyl-3-[4-Fluoro-2-(2-hydroxy-ethylimino)-3-(2,2,2-trifluoro-ethyl)    -2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   361.    (5R)-3-(3-tert-Butyl-2-methoxyimino-2,3-dihydro-benzothiazol-6-yl)-2-oxo    -5-oxazolidinecarboxamide

-   362.    (5R)-N-methyl-3-(3-tert-Butyl-2-methoxyimino-2,3-dihydro-benzothiazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   363.    (5R)-N-methyl-3-[4-Fluoro-2-methoxyimino-3-(2,2,2-trifluoro-ethyl)-2,3-dihydro-benzooxazol-6-yl]-2-oxo-5-oxazolidinecarboxamide

-   364.    (5R)-3-[4-tert-Butyl-3-(2-hydroxy-ethylimino)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide

-   365.    (5R)-N-methyl-3-[4-tert-Butyl-3-(2-hydroxy-ethylimino)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide

-   366.    (5R)-3-[4-tert-Butyl-5-fluoro-3-(2-hydroxy-ethylimino)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide-   367.    (5R)-N-methyl-3-[4-tert-Butyl-5-fluoro-3-(2-hydroxy-ethylimino)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-2-oxo-5-oxazolidinecarboxamide-   368.    (5R)-3-(4-tert-Butyl-3-methoxyimino-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   369.    (5R)-N-methyl-3-(4-tert-Butyl-3-methoxyimino-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   370.    (5R)-3-(4-tert-Butyl-5-fluoro-3-methoxyimino-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide

-   371.    (5R)-N-methyl-3-(4-tert-Butyl-5-fluoro-3-methoxyimino-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   372.    (5R)-3-(4-Fluoro-3-methyl-2-methylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   373.    (5R)-3-(3-Ethyl-4-fluoro-2-methylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   374.    (5R)-3-(4-Fluoro-3-isopropyl-2-methylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   375.    (5R)-N-methyl-3-(4-Fluoro-3-methyl-2-methylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   376.    (5R)-N-methyl-3-(3-Ethyl-4-fluoro-2-methylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   377.    (5R)-N-methyl-3-(4-Fluoro-3-isopropyl-2-methylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   378.    (5R)-3-(3-Isopropyl-2-methylimino-2,3-dihydro-benzooxazol-6-yl)-2-oxo-5-oxazolidinecarboxamide-   379.    (5R)-3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   380.    (5R)-N-methyl-3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   381.    (5R)-3-(4-Ethyl-5-fluoro-3-methoxyimino-3,4-dihydro-2-H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   382.    (5R)-3-(5-Fluoro-4-isopropyl-3-methoxyimino-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-2-oxo-5-oxazolidinecarboxamide-   383.    (5R)-3-[4-(1-Cyano-cylopropyl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   384.    (5R)-N-methyl-3-[4-(1-Cyano-cyclopropyl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinecarboxamide-   385.    (5R)-N-methyl-3-[3-Fluoro-4-(1-fluoro-cyclopropyl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   386.    (5R)-3-[3-Fluoro-4-(1-fluoro-cyclopropyl)-phenyl]-2-oxo-5-oxazolidinecarboxamide-   387.    (5R)-3-(4-Cyclopropyl-3-fluoro-phenyl)-2-oxo-5-oxazolidinecarboxamide-   388.    (5R)-3-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   389.    (5R)-3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   390.    (5R)-N-methyl-3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   391.    (5R)-3-(4,4,8-trifluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   392.    (5R)-N-methyl-3-(4,4,8-trifluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide-   393.    (5R)-3-(4,4-Difluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-5-oxazolidinecarboxamide    MIC Test Method

The in vitro MICs of test compounds are determined by a standard agardilution method. A stock drug solution of each analog is prepared in thepreferred solvent, usually DMSO:H₂O (1:3). Serial 2-fold dilutions ofeach sample are made using 1.0 ml aliquots of sterile distilled water.To each 1.0 ml aliquot of drug is added 9 ml of molten Mueller Hintonagar medium. The drug-supplemented agar is mixed, poured into 15×100 mmpetri dishes, and allowed to solidify and dry prior to inoculation.

Vials of each of the test organisms are maintained frozen in the vaporphase of a liquid nitrogen freezer. Test cultures are grown overnight at35° C. on the medium appropriate for the organism. Colonies areharvested with a sterile swab, and cell suspensions are prepared inTrypticase Soy broth (TSB) to equal the turbidity of a 0.5 McFarlandstandard. A 1:20 dilution of each suspension is made in TSB. The platescontaining the drug supplemented agar are inoculated with a 0.001 mldrop of the cell suspension using a Steers replicator, yieldingapproximately 10⁴ to 10⁵ cells per spot. The plates are incubatedovernight at 35° C.

Following incubation the Minimum Inhibitory Concentration (MIC μg/ml),the lowest concentration of drug that inhibits visible growth of theorganism, is read and recorded. The data is shown in Table I.

TABLE 1 MIC of Compounds of Formula I for Staphylococcus aureus (SAUR9213) Example No. MIC (μg/ml) 1 4 2 8 3 8 4 16 5 16 6 16 7 2 8 1 9 4 104 11 4 12 2 13 2 14 4 15 2 17 4 18 16 20 4 21 8 22 4 23 4 24 2 25 8 2616 27 8 29 1 30 1 31 1 32 1 33 4 34 8 35 2 36 2 37 2 38 1 39 1 40 4 41 242 4 43 4 44 4 45 4 46 8 47 4 48 2 49 8 50 2 51 2 52 2 53 2 54 0.5 55 156 4 57 8 58 8 59 2 60 2 61 8 62 4 63 4 64 0.5 65 2–4 66 4 67 2 68 4 692 70 2 71 4 72 2 73 2 74 8 75 8 76 4 77 2 78 8 79 1 80 2 81 4 82 1 83 284 2 85 2 86 4 87 2 88 4 89 16 90 4 91 4

1. A method for the treatment of microbial infections in mammalscomprising administration to said animal an effective amount of acompound of formula I, or a pharmaceutically acceptable salt thereof:

A is a structure i

C is aryl, wherein said aryl is phenyl or naphthyl, wherein said aryl isoptionally substituted with 1-3 of R₂; B is het or substituted het,provided that when C is phenyl optionally substituted with R₂ that B isnot

Q is independently selected from H, C₁-C₆ alkyl, —O—C₁-C₆ alkyl, phenyl,benzyl, —OH, CF₃, CCl₃, —NR₃R₃, —C₁-C₆ alkylene-NR₃R₃, C₁-C₆alkylene-(CH₂phenyl)-NR₃R₃, C₁-C₆ alkylene-(CH₂benzyl)-NR₃R₃, and

R₁ is selected from H, —OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino,substituted alkyl, substituted alkoxy, and substituted alkenyl; Each R₂is independently selected from H, alkyl, amino, NO₂, —CN, halo, andsubstituted alkyl; Each R₃ is independently selected from H or C₁-C₆alkyl; and W₂ is O or S.
 2. A method for the treatment of microbialinfections in mammals comprising administration to said animal aneffective amount of a compound of formula II, or a pharmaceuticallyacceptable salt thereof:

A is a structure i

B is het, or substituted het, provided that B is not

Q is independently selected from H, C₁-C₆ alkyl, —O—C₁-C₆ alkyl, phenyl,benzyl, —OH, CF₃, CCl₃, —NR₃R₃, —C₁-C₆ alkylene-NR₃R₃, C₁-C₆alkylene-(CH₂phenyl)-NR₃R₃, C₁-C₆ alkylene-(CH₂benzyl)-NR₃R₃, and

R₁ is selected from H, —OH, alkyl, cycloalkyl, alkoxy, alkenyl, amino,substituted alkyl, substituted alkoxy, and substituted alkenyl; Each R₂is independently selected from H, alkyl, amino, NO₂, —CN, halo, andsubstituted alkyl; Each R₃ is independently selected from H or C₁-C₆alkyl; and W₂ is O or S.
 3. The method of claim 2, wherein R₁ is H,—NH₂, —OH, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ alkoxy, or C₂₋₄ alkenyl,the alkyl, alkoxy and alkenyl each optionally being substituted with oneor more halo, —OH, —CN.
 4. The method of claim 3, wherein R₁ is H, —OH,—CH₂—CH═CH₂, methyl, ethyl, propyl, —CH₂—CH₂F, —CH₂—CH₂OH, or methoxy.